ClinVar Miner

Submissions for variant NM_002471.3(MYH6):c.3383G>A (p.Arg1128His) (rs376002621)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000658292 SCV000780063 uncertain significance not provided 2018-05-17 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MYH6 gene. The R1128H variant has not been published as pathogenic or been reported as benign to our knowledge. This variant was observed in 14/23,132 (0.06%) alleles from individuals of African ancestry in large population cohorts (Lek et al., 2016). The R1128H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000226348 SCV000287408 uncertain significance Familial hypertrophic cardiomyopathy 14 2017-04-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1128 of the MYH6 protein (p.Arg1128His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs376002621, ExAC 0.04%) but has not been reported in the literature in individuals with a MYH6-related disease. ClinVar contains an entry for this variant (Variation ID: 44482). 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. In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that this variant causes disease, but the evidence is insufficient at this time to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000037475 SCV000061133 uncertain significance not specified 2013-01-30 criteria provided, single submitter clinical testing The Arg1128His variant in MYH6 has not been reported in the literature nor previ ously identified by our laboratory. This variant has been identified in 2/4370 o f African American chromosomes from a broad population by the NHLBI Exome Sequen cing Project ( Computational analyses (bioche mical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) sugge st that the Arg1128His variant may impact the protein, though this information i s not predictive enough to determine pathogenicity. Additional information is n eeded to fully assess the clinical significance of the Arg1128His variant.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000622618 SCV000740624 uncertain significance Left ventricular noncompaction 2017-05-23 criteria provided, single submitter clinical testing

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