ClinVar Miner

Submissions for variant NM_002047.4(GARS1):c.880G>C (p.Gly294Arg) (rs137852643)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000327196 SCV000329356 pathogenic not provided 2016-08-30 criteria provided, single submitter clinical testing The G294R missense variant in the GARS gene has been previously published (reported as G240R due to use of alternative nomenclature) in two unrelated families with CMT2 (Antonellis et al., 2003). The G294R variant was not observed in approximately 5,900 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G294R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Functional analysis shows that G294R is located in the catalytic domain and disrupts heterodimer formation and inhibits aminoacylation (Nagle et al., 2007; He et al., 2011).
Invitae RCV000692132 SCV000819941 pathogenic Charcot-Marie-Tooth disease, type 2 2019-10-21 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 294 of the GARS protein (p.Gly294Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with Charcot-Marie-Tooth disease, type 2 (CMT2) and has been observed to segregate with disease in several families (PMID: 12690580, 8872480,10732809, Invitae). ClinVar contains an entry for this variant (Variation ID: 9204). This variant has also been reported as p.Gly240Arg. Experimental studies have shown that this missense change impairs heterodimer formation of the GARS protein leading to a loss of aminoacylation activity (PMID: 17595294, 21737751, 27008886, 26503042, 26138142, 17035524). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000009782 SCV000030003 pathogenic Charcot-Marie-Tooth disease type 2D 2003-05-01 no assertion criteria provided literature only
Inherited Neuropathy Consortium RCV000789142 SCV000928494 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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