ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2678C>A (p.Ala893Glu) (rs727503254)

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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,Partners HealthCare Personalized Medicine RCV000151259 SCV000199175 uncertain significance not specified 2015-06-10 criteria provided, single submitter clinical testing The p.Ala893Glu variant in MYH7 has been identified by our laboratory in 1 Cauca usian individual with HCM and segregated with disease in 1 affected family membe r. It was absent from large population studies; however, it is listed in dbSNP w ith no frequency data (rs727503254). Alanine (Ala) at position 893 is not conser ved in mammals or evolutionarily distant species and the change to glutamic acid (Glu) was predicted to be benign using a computational tool clinically validate d by our laboratory. This tool's benign prediction is estimated to be correct 89 % of the time (Jordan 2011). This variant is located in the last three bases of the exon, which is part of the 5' splice region. Computational tools do not sugg est an impact to splicing; however, this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Ala893G lu variant is uncertain.
Invitae RCV000557182 SCV000623678 uncertain significance Hypertrophic cardiomyopathy 2017-05-26 criteria provided, single submitter clinical testing This sequence change replaces alanine with glutamic acid at codon 893 of the MYH7 protein (p.Ala893Glu). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a MYH7-related disease. ClinVar contains an entry for this variant (Variation ID: 164319). A computational algorithm designed to assess the pathogenicity of variants in MYH7 with regard to hypertrophic cardiomyopathy predicted this sequence change to be tolerated. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). 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). In summary, this variant has uncertain impact on MYH7 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Blueprint Genetics RCV000788524 SCV000927673 likely pathogenic not provided 2018-05-03 criteria provided, single submitter clinical testing

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