ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2012G>A (p.Arg671His) (rs730880883)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000158824 SCV000208759 uncertain significance not provided 2014-07-01 criteria provided, single submitter clinical testing p.Arg671His (CGT>CAT): c.2012 G>A in exon 18 of the MYH7 gene (NM_000257.2). A variant of unknown significance has been identified in the MYH7 gene. The R671H variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The R671H 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 silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, missense mutations in the same residue (R671C) and in nearby residues (R663S, R663H, H668N) have been reported in association with cardiomyopathy, supporting the functional importance of this residue and this region of the protein. However, R671H is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in HCM panel(s).
Invitae RCV000702206 SCV000831050 likely pathogenic Hypertrophic cardiomyopathy 2018-03-15 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 671 of the MYH7 protein (p.Arg671His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 25132132, Invitae). ClinVar contains an entry for this variant (Variation ID: 181357). 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. A different missense substitution at this codon (p.Arg671Cys) has been determined to be pathogenic (PMID: 25132132, Invitae). This suggests that the arginine residue is critical for MYH7 protein function and that other missense substitutions at this position may also be pathogenic. 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, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000158824 SCV000924874 uncertain significance not provided 2016-11-09 no assertion criteria provided provider interpretation p.Arg671His (c.2012 G>A) in exon 18 of the MYH7 gene (NM_000257.2) Seen in a patient in our center with HCM and a family history of HCM. Tested at GeneDx. Given the lack of case data, position, and apparent rarity, we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). I could find no cases of this variant reported in association with disease. The only submission in ClinVar is from the testing lab (as of Nov 9th, 2016). The variant is not present in the current SHaRe dataset (as of Nov 9th, 2016). The variant is in the head of myosin, which is enriched for pathogenic variation. However, when our team dissected which portions of the head are enriched for pathogenic variation this amino acid position did not come up as enriched in cases (Homburger et al 2016). There is no variation at codon 671 listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. The average coverage at that site in gnomAD doe snot seem to be available, however coverage at a neighboring variant is good and the read data for that variant suggests that there is good coverage at this site as well. The variant is also not in ExAC and median coverage is 50x.

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