ClinVar Miner

Submissions for variant NM_003680.3(YARS1):c.586G>A (p.Glu196Lys) (rs121908834)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000006566 SCV000814860 pathogenic Charcot-Marie-Tooth disease, dominant intermediate C 2019-07-11 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 196 of the YARS protein (p.Glu196Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with dominant intermediate Charcot-Marie-Tooth disease, type C in a family (PMID: 14606043, 16429158). ClinVar contains an entry for this variant (Variation ID: 6189). Experimental studies have shown that this missense change introduced into a Drosophila model induces an impairment of motor performance and a decrease in translation of YARS mRNA (PMID: 19561293, 26138142). Additionally, yeast complimentation assays showed a reduction of growth in cultures carrying this variant (PMID: 26975778). A different missense substitution at this codon (p.Glu196Gln) has been determined to be likely pathogenic (PMID: 26257172). This suggests that the glutamic acid residue is critical for YARS protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000006566 SCV000026749 pathogenic Charcot-Marie-Tooth disease, dominant intermediate C 2006-02-01 no assertion criteria provided literature only
Inherited Neuropathy Consortium RCV000789621 SCV000928987 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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