ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.1003G>C (p.Ala335Pro) (rs727503272)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000443440 SCV000536371 likely pathogenic not provided 2018-11-29 criteria provided, single submitter clinical testing A A335P variant that is likely pathogenic was identified in the MYH7 gene. It has not been published as pathogenic or been reported as benign to our knowledge. However, this variant has been shown to segregate with disease in several family members referred to genetic testing at GeneDx The A335P variant is not observed in large population cohorts (Lek et al., 2016). The A335P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. This variant is located in the myosin motor domain, a region enriched with missense variants reported in association with HCM (Walsh et al., 2017; Kelly et al., 2018). In summary, A335P in the MYH7 gene is interpreted as a likely pathogenic variant.
Invitae RCV000463059 SCV000546230 uncertain significance Hypertrophic cardiomyopathy 2018-07-11 criteria provided, single submitter clinical testing This sequence change replaces alanine with proline at codon 335 of the MYH7 protein (p.Ala335Pro). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and proline. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MYH7-related disease. ClinVar contains an entry for this variant (Variation ID: 393021). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or 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). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000443440 SCV000924871 uncertain significance not provided 2016-10-12 no assertion criteria provided provider interpretation The testing lab was Invitae. Given that this is a novel variant, we also consider this a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Per the lab report and our own searches, there is no case data available for this variant. It is not currently listed in ClinVar or in SHaRe. In silico prediction models predict that this variant is probably damaging. Another variant has been reported in association with disease at this codon (p.Ala335Ser), but is reported as a variant of uncertain significance in ClinVar. This patient’s variant, p.Ala335Pro, does not fall within the regions of MYH7 that are enriched for pathogenic variation (Homburger et al 2016). In total the variant has not been seen in laboratory controls, published controls and individuals from publicly available population datasets. There is no variation at codon 335 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of October 2016). The average coverage at that site in ExAC is 60x.

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