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NM_002047.4(GARS1):c.979G>A (p.Gly327Arg) AND Charcot-Marie-Tooth disease type 2

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Apr 25, 2022
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:
RCV000819141.6

Allele description [Variation Report for NM_002047.4(GARS1):c.979G>A (p.Gly327Arg)]

NM_002047.4(GARS1):c.979G>A (p.Gly327Arg)

Gene:
GARS1:glycyl-tRNA synthetase 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
7p14.3
Genomic location:
Preferred name:
NM_002047.4(GARS1):c.979G>A (p.Gly327Arg)
HGVS:
  • NC_000007.14:g.30612193G>A
  • NG_007942.1:g.22629G>A
  • NM_001316772.1:c.817G>A
  • NM_002047.4:c.979G>AMANE SELECT
  • NP_001303701.1:p.Gly273Arg
  • NP_002038.2:p.Gly327Arg
  • LRG_243t1:c.979G>A
  • LRG_243:g.22629G>A
  • NC_000007.13:g.30651809G>A
  • NM_002047.2:c.979G>A
  • NM_002047.3:c.[979G>A]
Protein change:
G273R
Links:
dbSNP: rs1584034430
NCBI 1000 Genomes Browser:
rs1584034430
Molecular consequence:
  • NM_001316772.1:c.817G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002047.4:c.979G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Charcot-Marie-Tooth disease type 2
Synonyms:
Charcot-Marie-Tooth, Type 2
Identifiers:
MONDO: MONDO:0018993; MedGen: C0270914

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000959785Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Apr 25, 2022) 		germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Application of targeted multi-gene panel testing for the diagnosis of inherited peripheral neuropathy provides a high diagnostic yield with unexpected phenotype-genotype variability.

Antoniadi T, Buxton C, Dennis G, Forrester N, Smith D, Lunt P, Burton-Jones S.

BMC Med Genet. 2015 Sep 21;16:84. doi: 10.1186/s12881-015-0224-8.

PubMed [citation]
PMID:
26392352
PMCID:
PMC4578331

Clinical and Genetic Features in a Series of Eight Unrelated Patients with Neuropathy Due to Glycyl-tRNA Synthetase (GARS) Variants.

Forrester N, Rattihalli R, Horvath R, Maggi L, Manzur A, Fuller G, Gutowski N, Rankin J, Dick D, Buxton C, Greenslade M, Majumdar A.

J Neuromuscul Dis. 2020;7(2):137-143. doi: 10.3233/JND-200472.

PubMed [citation]
PMID:
31985473
See all PubMed Citations (4)

Details of each submission

From Invitae, SCV000959785.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

For these reasons, this variant has been classified as Pathogenic. This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 327 of the GARS protein (p.Gly327Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary motor neuropathy (PMID: 26392352, 31628756, 31985473; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 661670). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects GARS function (PMID: 31628756). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site.

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

Last Updated: Apr 6, 2024