NM_002047.4(GARS1):c.1415A>G (p.His472Arg) AND Charcot-Marie-Tooth disease type 2

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 8, 2023
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:: RCV000459084.9

Allele description [Variation Report for NM_002047.4(GARS1):c.1415A>G (p.His472Arg)]

NM_002047.4(GARS1):c.1415A>G (p.His472Arg)

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.1415A>G (p.His472Arg)

HGVS:

NC_000007.14:g.30621448A>G
NG_007942.1:g.31884A>G
NM_001316772.1:c.1253A>G
NM_002047.4:c.1415A>GMANE SELECT
NP_001303701.1:p.His418Arg
NP_002038.2:p.His472Arg
LRG_243t1:c.1415A>G
LRG_243:g.31884A>G
NC_000007.13:g.30661064A>G
NM_002047.1:c.1253A>G
NM_002047.2:c.1415A>G
NM_002047.3:c.1415A>G
p.His418Arg

Protein change:

H418R; HIS472ARG

Links:

OMIM: 600287.0013; dbSNP: rs1060502838

NCBI 1000 Genomes Browser:

rs1060502838

Molecular consequence:

NM_001316772.1:c.1253A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_002047.4:c.1415A>G - 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
SCV000550942	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 8, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 16014653, 24627108, 25168514, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000550942

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 8, 2023)

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

Phenotypic spectrum of disorders associated with glycyl-tRNA synthetase mutations.

Sivakumar K, Kyriakides T, Puls I, Nicholson GA, Funalot B, Antonellis A, Sambuughin N, Christodoulou K, Beggs JL, Zamba-Papanicolaou E, Ionasescu V, Dalakas MC, Green ED, Fischbeck KH, Goldfarb LG.

Brain. 2005 Oct;128(Pt 10):2304-14. Epub 2005 Jul 13.

PubMed [citation]

PMID:: 16014653

Whole-exome sequencing in patients with inherited neuropathies: outcome and challenges.

Schabhüttl M, Wieland T, Senderek J, Baets J, Timmerman V, De Jonghe P, Reilly MM, Stieglbauer K, Laich E, Windhager R, Erwa W, Trajanoski S, Strom TM, Auer-Grumbach M.

J Neurol. 2014 May;261(5):970-82. doi: 10.1007/s00415-014-7289-8. Epub 2014 Mar 15.

PubMed [citation]

PMID:: 24627108

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000550942.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 472 of the GARS protein (p.His472Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with peripheral neuropathy (PMID: 16014653, 24627108). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 410314). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GARS protein function. Experimental studies have shown that this missense change affects GARS function (PMID: 25168514). For these reasons, this variant has been classified as Pathogenic.

#	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: Nov 3, 2024

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