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NM_004539.4(NARS1):c.32G>C (p.Arg11Pro) AND Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
May 10, 2021
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV001267638.2

Allele description [Variation Report for NM_004539.4(NARS1):c.32G>C (p.Arg11Pro)]

NM_004539.4(NARS1):c.32G>C (p.Arg11Pro)

Gene:
NARS1:asparaginyl-tRNA synthetase 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
18q21.31
Genomic location:
Preferred name:
NM_004539.4(NARS1):c.32G>C (p.Arg11Pro)
HGVS:
  • NC_000018.10:g.57620630C>G
  • NM_004539.4:c.32G>CMANE SELECT
  • NP_004530.1:p.Arg11Pro
  • NC_000018.9:g.55287862C>G
Protein change:
R11P; ARG11PRO
Links:
OMIM: 108410.0005; dbSNP: rs771435243
NCBI 1000 Genomes Browser:
rs771435243
Molecular consequence:
  • NM_004539.4:c.32G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities
Identifiers:
MONDO: MONDO:0100348; MedGen: C5436783; OMIM: 619091

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001445822OMIM
no assertion criteria provided
Pathogenic
(Nov 18, 2020) 		germlineliterature only

PubMed (1)
[See all records that cite this PMID]

SCV001593244SIB Swiss Institute of Bioinformatics
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(May 10, 2021) 		unknowncuration

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownunknownnot providednot providednot providednot providednot providedcuration
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only

Citations

PubMed

De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects.

Manole A, Efthymiou S, O'Connor E, Mendes MI, Jennings M, Maroofian R, Davagnanam I, Mankad K, Lopez MR, Salpietro V, Harripaul R, Badalato L, Walia J, Francklyn CS, Athanasiou-Fragkouli A, Sullivan R, Desai S, Baranano K, Zafar F, Rana N, Ilyas M, Horga A, et al.

Am J Hum Genet. 2020 Aug 6;107(2):311-324. doi: 10.1016/j.ajhg.2020.06.016. Epub 2020 Jul 31.

PubMed [citation]
PMID:
32738225
PMCID:
PMC7413890

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From OMIM, SCV001445822.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)

Description

In 2 sibs from Kosovo (family 16) with neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities (NEDMILG; 619091), Manole et al. (2020) identified a homozygous c.32G-C transversion (c.32G-C, NM_004539.4) in the NARS1 gene, resulting in an arg11-to-pro (R11P) substitution at the 5-prime end of the noncanonical UNE-N domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was found once in heterozygous state in the gnomAD database. Patient cells showed decreased NARS1 protein levels and a mild decrease in enzymatic activity (80% of controls). The authors suggested that this domain may have nontranslational functions that contribute to the phenotype. The patients had a severe form of the disorder with early-onset seizures and cerebral atrophy and delayed myelination on brain imaging.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From SIB Swiss Institute of Bioinformatics, SCV001593244.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (2)

Description

This variant is interpreted as a variant of uncertain significance for Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, autosomal recessive. The following ACMG Tag(s) were applied: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (PM2); Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1); Well-established functional studies show a deleterious effect (PS3 downgraded to supporting).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Apr 23, 2022

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