ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.1504A>G (p.Lys502Glu)

dbSNP: rs876657877
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000218204 SCV000272033 uncertain significance not specified 2015-03-21 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Lys502Glu variant in MYH7 has not been previously reported in individuals with cardiomyop athy or in large population studies. Lysine (Lys) at position 502 is highly cons erved in mammals and across evolutionarily distant species and the change to glu tamic acid (Glu) was predicted to be pathogenic using a computational tool clini cally validated by our laboratory. This tool's pathogenic prediction is estimate d to be correct 94% of the time (Jordan 2011). In summary, while there is some s uspicion for a pathogenic role, the clinical significance of the p.Lys502Glu var iant is uncertain.
Invitae RCV000628909 SCV000749817 uncertain significance Hypertrophic cardiomyopathy 2017-10-31 criteria provided, single submitter clinical testing This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). This variant is not present in population databases (ExAC no frequency). 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. A computational algorithm designed to assess the pathogenicity of variants in MYH7 with regard to hypertrophic cardiomyopathy predicted this sequence change to be deleterious. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). This variant has not been reported in the literature in individuals with MYH7-related disease. ClinVar contains an entry for this variant (Variation ID: 228899). This sequence change replaces lysine with glutamic acid at codon 502 of the MYH7 protein (p.Lys502Glu). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamic acid.
GeneDx RCV001753645 SCV002007421 uncertain significance not provided 2019-09-26 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance by other clinical laboratories (ClinVar Variant ID# 228899; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect

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