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

dbSNP: rs1060502838

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000459084	SCV000550942	pathogenic	Charcot-Marie-Tooth disease type 2	2023-12-08	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV002461198	SCV002755192	pathogenic	Inborn genetic diseases	2019-11-13	criteria provided, single submitter	clinical testing	The p.H472R variant (also known as c.1415A>G), located in coding exon 11 of the GARS gene, results from an A to G substitution at nucleotide position 1415. The histidine at codon 472 is replaced by arginine, an amino acid with highly similar properties. This variant (also referred to as p.H418R) has been reported in multiple patients with distal hereditary motor neuropathy (also called distal spinal muscular atrophy) and has been shown to segregate with disease (Sivakumar K et al. Brain, 2005 Oct;128:2304-14; Schabhüttl M et al. J. Neurol., 2014 May;261:970-82; Karakaya M et al. Hum. Mutat., 2018 09;39:1284-1298). Functional studies of this alteration demonstrate reduced aminoacylation activity, substantial reductions in yeast viability, and altered cellular localization in transfected mouse motor neuron cell lines (Griffin LB et al. Hum. Mutat., 2014 Nov;35:1363-71; Antonellis A et al. J. Neurosci., 2006 Oct;26:10397-406). In addition to the clinical data presented in the literature, this alteration is absent in population-based cohorts in the Genome Aggregation Database (gnomAD) and predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Institute of Human Genetics, Cologne University	RCV000664213	SCV000787774	pathogenic	Neuronopathy, distal hereditary motor, type 5A	2018-04-25	no assertion criteria provided	clinical testing
Inherited Neuropathy Consortium	RCV000789777	SCV000929161	uncertain significance	Charcot-Marie-Tooth disease		no assertion criteria provided	literature only
Inherited Neuropathy Consortium	RCV000790256	SCV000929656	uncertain significance	Distal spinal muscular atrophy		no assertion criteria provided	literature only
OMIM	RCV000664213	SCV001451405	pathogenic	Neuronopathy, distal hereditary motor, type 5A	2014-11-01	no assertion criteria provided	literature only
GeneReviews	RCV003332179	SCV001760936	not provided	Charcot-Marie-Tooth disease type 2D		no assertion provided	literature only	GARS1-HMSN (exclusively dSMA-V) [Sivakumar et al 2005, Griffin et al 2014, Cortese et al 2020, Lin et al 2020]
Inherited Neuropathy Consortium Ii, University Of Miami	RCV003332179	SCV004174564	uncertain significance	Charcot-Marie-Tooth disease type 2D	2019-04-20	no assertion criteria provided	literature only