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

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000203886	SCV000260521	uncertain significance	Charcot-Marie-Tooth disease, dominant intermediate C	2019-05-28	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