ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2191C>T (p.Pro731Ser) (rs727504299)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000158517 SCV000208452 pathogenic not provided 2012-05-11 criteria provided, single submitter clinical testing p.Pro731Ser (CCT>TCT): c.2191 C>T in exon 20 of the MYH7 gene (NM_000257.2). The Pro731Ser mutation in the MYH7 gene has not been reported previously as a disease-causing mutation or as a benign polymorphism to our knowledge. Pro731Ser results in a non-conservative amino acid substitution of a non-polar, sterically constrained Proline with a neutral, polar Serine at a position that is highly conserved in vertebrates. Missense mutations at the same codon (Pro731Leu) and at nearby codons (Ala728Val, Ala729Pro, Gly733Arg, Gly733Glu, Gln734Glu) have been reported in association with cardiomyopathy, supporting the functional importance of this residue and this region of the protein. In addition, the NHLBI ESP Exome Variant Server reports Pro731Ser was not observed in approximately 5000 control samples from individuals of European and African American backgrounds indicating it is not a common, benign variant in these populations. Finally, in-silico analysis predicts Pro731Ser to be damaging to protein structure/function. Therefore, Pro731Ser in the MYH7 gene is interpreted to be a likely disease-causing mutation. The variant is found in HCM panel(s).
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000201447 SCV000256151 likely pathogenic Familial hypertrophic cardiomyopathy 1 criteria provided, single submitter clinical testing
Invitae RCV001226065 SCV001398361 pathogenic Hypertrophic cardiomyopathy 2019-10-15 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 731 of the MYH7 protein (p.Pro731Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals with hypertrophic cardiomyopathy (HCM) and observed to segregate with HCM in a family (PMID: 23283745, 25078086, 24093860, 25327599). ClinVar contains an entry for this variant (Variation ID: 181176). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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). For these reasons, this variant has been classified as Pathogenic.

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