ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2555T>C (p.Met852Thr) (rs397516157)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000557637 SCV000059456 likely pathogenic Hypertrophic cardiomyopathy 2019-01-31 criteria provided, single submitter clinical testing The p.Met852Thr variant in MYH7 has been reported in 5 individuals with HCM (Richard 2003, Morita 2008, Marsiglia 2013, Walsh 2016, LMM unpublished data). This variant has also been identified in 1/15420 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs397516157). Methionine (Met) at position 852 is highly conserved in mammals and across evolutionarily distant species and the change to threonine (Thr) was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). Additionally, this variant lies in the head region of the protein. Missense variants in this region have been reported and statistically indicated to be more likely to cause disease (Walsh 2016). In summary, although additional studies are required to fully establish its clinical significance, the p.Met852Thr variant is likely pathogenic. ACMG/AMP Criteria applied: PM1; PM2; PP3; PS4_Supporting.
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000201446 SCV000256148 likely pathogenic Familial hypertrophic cardiomyopathy 1 criteria provided, single submitter clinical testing
Invitae RCV000557637 SCV000623672 pathogenic Hypertrophic cardiomyopathy 2018-06-26 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 852 of the MYH7 protein (p.Met852Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with hypertrophic cardiomyopathy and familial left ventricular hypertrophy (PMID: 12707239, 27247418, 24093860, 18403758). ClinVar contains an entry for this variant (Variation ID: 42916). 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). An algorithm developed specifically for the MYH7 gene (PMID: 21310275), suggest that this missense change is likely to be deleterious. However, this prediction has not been confirmed by published functional studies and their clinical significance is uncertain. A different missense substitution at this codon (p.Met852Arg) has been determined to be pathogenic (PMID: 20800588, 27532257). This suggests that the methionine residue is critical for MYH7 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.

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