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:: RCV000819141.7

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000959785	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 25, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 26392352, 31985473, 31628756, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000959785

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Apr 25, 2022)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000959785.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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