ClinVar Miner

Submissions for variant NM_000432.3(MYL2):c.488A>G (p.Glu163Gly) (rs397516407)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000158908 SCV000208843 likely pathogenic not provided 2013-08-27 criteria provided, single submitter clinical testing This variant is denoted p.Glu163Gly (GAA>GGA): c.488 A>G in exon 7 of the MYL2 gene (NM_000432.3). The Glu163Gly variant in the MYL2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Glu163Gly results in a non-conservative amino acid substitution of a negatively charged Glutamic acid with a non-polar Glycine at a position that is conserved across species. In silico analysis predicts Glu163Gly is damaging to the protein structure/function. Mutations in nearby residues (Gly162Arg, Asp166Val) have been reported in association with HCM, further supporting the functional importance of this region of the protein. Furthermore, the Glu163Gly variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, while Glu163Gly is a good candidate for a disease-causing mutation, with the clinical and molecular information available at this time we cannot unequivocally determine the clinical significance of this variant. The variant is found in HCM panel(s).
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000223748 SCV000280387 uncertain significance not specified 2013-04-09 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Glu163Gly (c.488A>G). To the best of our knowledge, this p.Glu163Gly variant is novel and has not been reported in association with disease or in publicly available general population datasets. This variant results in a non-conservative amino acid substitution, where a negatively charged glutamic acid is exchanged for a nonpolar glycine. The glutamic acid at this position is completely conserved in available primates and other vertebrates, as are neighboring amino acids. In silico models consistently predict this variant to be damaging (including PolyPhen and Mutation Taster). Variants in nearby residues and at this exact residue have been reported in association with HCM in the literature and per report by an outside clinical laboratory, including Gly161Arg, Gly162Arg, Asp166Ala and Gly162Glu. A variant at the same residue, p.Glu163Ala, currently considered likely pathogenic by the LMM is currently in ClinVar (SCV000060064). This variant has been seen in two unrelated families with HCM by the LMM. No details regarding segregation with disease or whether alternative variants were detected in those families were reported. LMM reports that they have not seen this patient’s p.Glu163Gly variant to date. Pathogenic variants in the MYL2 gene, which encodes myosin regulatoray light chain 2, have been reported in association with HCM in the literature; however it is not known what percentage of individuals with familial HCM have a pathogenic variant in this gene. In total, this variant has not been seen in ~6500 individuals from publicly available population datasets. There is no variation at codon 163 listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~6500 individuals of European and African American descent (as of January 8, 2015). Note, this does not match the patient’s ancestry (Mexico). There is also no variation at this codon listed in the Broad ExAC database, which includes variant calls on 65,000 individuals of varying ancestries (including 5,795 individuals with reported Latino ancestry). There is also no variation at this codon in dbSNP or 1000Genomes (as of January 8, 2015).

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