ClinVar Miner

Submissions for variant NM_003680.3(YARS1):c.1571G>C (p.Gly524Ala) (rs201687117)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000203886 SCV000260521 uncertain significance Charcot-Marie-Tooth disease, dominant intermediate C 2020-08-08 criteria provided, single submitter clinical testing This sequence change replaces glycine with alanine at codon 524 of the YARS protein (p.Gly524Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. This variant is present in population databases (rs201687117, ExAC 0.005%). This variant has not been reported in the literature in individuals with YARS-related conditions. ClinVar contains an entry for this variant (Variation ID: 220175). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C0). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000523644 SCV000620226 uncertain significance not provided 2017-08-28 criteria provided, single submitter clinical testing The G524A variant in the YARS gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant is observed in 3/66,476 alleles (0.0045%) from individuals of non-Finnish European background in the ExAC dataset, with no homozygous control individuals reported (Lek et al., 2016). The G524A variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In addition, a missense variant in a neighboring residue (G525R) has been reported in the Human Gene Mutation Database in association with an autosomal recessive YARS-related disorder (Stenson et al., 2014). We interpret G524A as a variant of uncertain significance.
Fulgent Genetics,Fulgent Genetics RCV000203886 SCV000896354 uncertain significance Charcot-Marie-Tooth disease, dominant intermediate C 2018-10-31 criteria provided, single submitter clinical testing

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