ClinVar Genomic variation as it relates to human health
NM_016955.4(SEPSECS):c.715G>A (p.Ala239Thr)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_016955.4(SEPSECS):c.715G>A (p.Ala239Thr)
Variation ID: 18401 Accession: VCV000018401.8
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4p15.2 4: 25152049 (GRCh38) [ NCBI UCSC ] 4: 25153671 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline May 8, 2015 Feb 14, 2024 Dec 2, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_016955.4:c.715G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_058651.3:p.Ala239Thr missense NC_000004.12:g.25152049C>T NC_000004.11:g.25153671C>T NG_028222.1:g.13534G>A Q9HD40:p.Ala239Thr - Protein change
- A239T
- Other names
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- Canonical SPDI
- NC_000004.12:25152048:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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SEPSECS | - | - |
GRCh38 GRCh37 |
548 | 613 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 19, 2022 | RCV000000437.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 2, 2023 | RCV001380417.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 16, 2021 | RCV001582489.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Jan 19, 2022)
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criteria provided, single submitter
Method: clinical testing
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Pontocerebellar hypoplasia type 2D
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002811554.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Likely pathogenic
(Sep 30, 2020)
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criteria provided, single submitter
Method: research
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Pontocerebellar hypoplasia type 2D
Affected status: yes
Allele origin:
maternal
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Institute of Human Genetics, Cologne University
Accession: SCV001441232.1
First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020 |
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Pathogenic
(Aug 16, 2021)
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criteria provided, single submitter
Method: clinical testing
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Pontoneocerebellar hypoplasia
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001821286.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
Variant summary: SEPSECS c.715G>A (p.Ala239Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: SEPSECS c.715G>A (p.Ala239Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 252236 control chromosomes (gnomAD and publication data). This frequency is not significantly higher than expected for a pathogenic variant in SEPSECS causing Pontocerebellar Hypoplasia, Type 2D (4.4e-05 vs 0.0011), allowing no conclusion about variant significance. c.715G>A has been reported in the literature in individuals affected with progressive cerebellocerebral atrophy or progressive axonal polyneuropathy (Agamy_2010, Iwama_2016, Keller_2021). These data indicate that the variant is likely to be associated with disease. At least two functional studies report experimental evidence evaluating an impact on protein function and this variant caused complete inactivity of SEPSECS due to it's insolubility and inability to form productive tetramers (Agamy_2010, Puppala_2016). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic and likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Dec 02, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001578482.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 239 of the SEPSECS protein (p.Ala239Thr). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 239 of the SEPSECS protein (p.Ala239Thr). This variant is present in population databases (rs267607035, gnomAD 0.01%). This missense change has been observed in individual(s) with progressive cerebellocerebral atrophy (PMID: 20920667). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 18401). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SEPSECS protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects SEPSECS function (PMID: 20920667, 27576344). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 08, 2010)
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no assertion criteria provided
Method: literature only
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PONTOCEREBELLAR HYPOPLASIA, TYPE 2D
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000020585.2
First in ClinVar: Apr 04, 2013 Last updated: May 08, 2015 |
Comment on evidence:
For discussion of the ala239-to-thr (A239T) mutation in the SEPSECS gene that was found in compound heterozygous state in patients with pontocerebellar hypoplasia type 2D … (more)
For discussion of the ala239-to-thr (A239T) mutation in the SEPSECS gene that was found in compound heterozygous state in patients with pontocerebellar hypoplasia type 2D (PCH2D; 613811) by Agamy et al. (2010), see 613009.0001. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Genomic variants causing mitochondrial dysfunction are common in hereditary lower motor neuron disease. | Keller N | Human mutation | 2021 | PMID: 33600046 |
Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes. | Capalbo A | PLoS genetics | 2019 | PMID: 31589614 |
Consequences of mutations and inborn errors of selenoprotein biosynthesis and functions. | Fradejas-Villar N | Free radical biology & medicine | 2018 | PMID: 29709707 |
Structural basis for early-onset neurological disorders caused by mutations in human selenocysteine synthase. | Puppala AK | Scientific reports | 2016 | PMID: 27576344 |
Why 21? The significance of selenoproteins for human health revealed by inborn errors of metabolism. | Schweizer U | FASEB journal : official publication of the Federation of American Societies for Experimental Biology | 2016 | PMID: 27473727 |
Expanding preconception carrier screening for the Jewish population using high throughput microfluidics technology and next generation sequencing. | Gal M | BMC medical genomics | 2016 | PMID: 27175728 |
Milder progressive cerebellar atrophy caused by biallelic SEPSECS mutations. | Iwama K | Journal of human genetics | 2016 | PMID: 26888482 |
The Israeli national population program of genetic carrier screening for reproductive purposes. | Zlotogora J | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 25880436 |
Status quo of annotation of human disease variants. | Venselaar H | BMC bioinformatics | 2013 | PMID: 24305467 |
The population genetics of the Jewish people. | Ostrer H | Human genetics | 2013 | PMID: 23052947 |
Synthesis and decoding of selenocysteine and human health. | Schmidt RL | Croatian medical journal | 2012 | PMID: 23275319 |
Mutations disrupting selenocysteine formation cause progressive cerebello-cerebral atrophy. | Agamy O | American journal of human genetics | 2010 | PMID: 20920667 |
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Text-mined citations for rs267607035 ...
HelpRecord last updated Feb 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.