ClinVar Miner

Submissions for variant NM_003680.3(YARS1):c.586G>C (p.Glu196Gln) (rs121908834)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000235060 SCV000292349 likely pathogenic Charcot-Marie-Tooth disease, dominant intermediate C 2015-08-18 criteria provided, single submitter research Likely pathogenic based on segregation with the phenotype in a pedigree with dominant intermediate CMT, and based on conservation and prediction scores (Phylop, Polyphen, SIFT, MutationTaster).
Invitae RCV000235060 SCV000762165 pathogenic Charcot-Marie-Tooth disease, dominant intermediate C 2019-02-27 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glutamine at codon 196 of the YARS protein (p.Glu196Gln). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with Charcot-Marie-Tooth disease, type I in a single family (PMID: 26257172) and has been reported in several affected individuals (Invitae). ClinVar contains an entry for this variant (Variation ID: 243071). Yeast complimentation assays with this missense change show a reduction in growth, which suggests that this variant is a hypomorphic allele (PMID: 26257172). Variants that disrupt the p.Glu196 amino acid residue in YARS have been observed in affected individuals (PMID: 16429158, 19561293). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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