ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2782G>A (p.Asp928Asn) (rs727503252)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000527742 SCV000199167 likely pathogenic Hypertrophic cardiomyopathy 2014-08-26 criteria provided, single submitter clinical testing The Asp928Asn variant in MYH7 has been reported in 3 individuals with HCM and se gregated with disease in at least 2 affected relatives from 2 families (Erdmann 2003, Perrot 2005, Gimeno 2009). In addition, this variant has also been identif ied by our laboratory in 2 individuals with HCM and segregated with disease in 2 affected relatives. It has not been identified in large population studies. Com putational prediction tools and conservation analysis do not provide strong supp ort for or against an impact to the protein. In summary, although additional stu dies are required to fully establish its clinical significance, its absence in c ontrol populations and segregation with disease support that this variant is lik ely pathogenic.
GeneDx RCV000158574 SCV000208509 pathogenic not provided 2018-05-01 criteria provided, single submitter clinical testing The D928N pathogenic variant in the MYH7 gene has been previously reported in association with HCM (Erdmann et al., 2003; Perrot et al., 2005; Gimeno et al., 2009; Walsh et al., 2017; Weissler-Snir et al., 2017). The D928N variant was reported in one individual with severe HCM who also harbored a variant in the TNNT2 gene (Gimeno et al., 2009). In this family, carriers of both MYH7 D928N and the TNNT2 variant had a moderate or severe HCM phenotype, suggesting a possible additive effect (Gimeno et al., 2009). D928N has been observed in multiple unrelated individuals referred for cardiomyopathy testing at GeneDx, and segregated with an HCM phenotype in at least four individuals within one family in the absence of any other disease-causing variants. The D928N variant is not observed in large population cohorts (Lek et al., 2016). The D928N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Moreover, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. A missense variant in the same residue (D928V) and missense variants in nearby residues (E924K, E927K, E930Q, E930K, E931K) have also been reported in association with HCM, supporting the functional importance of this residue and this region of the protein (Michels et al., 2009; Stenson et al., 2014). In summary, D928N in the MYH7 gene is interpreted as a pathogenic variant.
Invitae RCV000527742 SCV000623684 pathogenic Hypertrophic cardiomyopathy 2018-11-16 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 928 of the MYH7 protein (p.Asp928Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with hypertrophic cardiomyopathy and has been shown to segregate with the disease in one family (PMID: 12974739, 15856146, 20038417, 27532257, 28193612). ClinVar contains an entry for this variant (Variation ID: 164313). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Ambry Genetics RCV000622071 SCV000740215 likely pathogenic Cardiovascular phenotype 2019-09-24 criteria provided, single submitter clinical testing Rarity in general population databases (dbsnp, esp, 1000 genomes);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Other data supporting pathogenic classification

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