ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.5344A>G (p.Met1782Val) (rs727504385)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000168424 SCV000219120 likely pathogenic Hypertrophic cardiomyopathy 2018-08-20 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 1782 of the MYH7 protein (p.Met1782Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. This variant is not present in population databases (rs727504385, ExAC no frequency). This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 26914223, 25611685, 27247418, 27532257, Invitae). ClinVar contains an entry for this variant (Variation ID: 177892). A computational algorithm designed to assess the pathogenicity of variants in MYH7 with regard to hypertrophic cardiomyopathy predicted this sequence change to be deleterious. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). However, this prediction has not been confirmed by published functional studies. 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.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000154544 SCV000204217 uncertain significance not specified 2015-11-13 no assertion criteria provided clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000786171 SCV000924876 uncertain significance not provided 2016-09-12 no assertion criteria provided provider interpretation p.Met1782Val (c.5344A>G) in the MYH7 gene (NM_000257.3) We have seen this variant in one Caucasian individual with HCM. Given the location, absence from population databases and presence in a small number of affected patients (but without segregation or functional data), we consider this variant a variant of uncertain significance, probably disease causing and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least 3 unrelated cases of hypertrophic cardiomyopathy (HCM) (not including this patient's family). There is weak case data. A 2015 study by Alfares et al assessed 2912 unrelated nonsyndromic HCM probands and 1209 family members referred between 2004 and 2013. Testing of up to 51 genes associated with HCM was conducted. The variant of interest was identified in a single proband and classified as “likely pathogenic,” though segregation information is not available. Per the Invitae report: “This variant has been observed in two unrelated patients with obstructive HCM who had positive family histories (Invitae database).” The variant is not in the head (the head is enriched for pathogenic variation). In addition, the variant is not in any of the regions we found enriched for pathogenic variation when comparing HCM patients to ExAC (Homburger et al 2016). There is no variation at codon 1782 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 4/12/16). Median coverage at that site is 100.

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