ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2539_2541del (p.Lys847del) (rs397516155)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000248308 SCV000318335 uncertain significance Cardiovascular phenotype 2013-03-05 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000143922 SCV000188799 likely pathogenic Primary familial hypertrophic cardiomyopathy 2014-09-01 no assertion criteria provided clinical testing
ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel, RCV000168354 SCV000564431 likely pathogenic Hypertrophic cardiomyopathy 2016-12-15 reviewed by expert panel curation The c.2539_2541del (p.Lys847del) variant in MYH7 has been reported in >15 individuals with hypertrophic cardiomyopathy (PS4; PMID:15358028; PMID:22429680; PMID:23233322; PMID:24093860; PMID:18258667; SHaRe consortium, PMID: 30297972; Partners LMM ClinVar SCV000059453.5; Invitae ClinVar SCV000219043.3). This variant segregated with disease in 3 affected individuals (PP1; Partners LMM ClinVar SCV000059453.5). This variant was absent from large population studies (PM2; http://exac.broadinstitute.org). This variant is a deletion of 1 amino acid at position 847 and is not predicted to alter the protein reading-frame (PM4). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PM2; PM4; PP1
Invitae RCV000168354 SCV000219043 pathogenic Hypertrophic cardiomyopathy 2018-11-08 criteria provided, single submitter clinical testing This variant, c.2539_2541delAAG, results in the deletion of 1 amino acid(s) of the MYH7 protein (p.Lys847del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with hypertrophic cardiomyopathy (PMID: 15358028, 22429680, 23233322, 24093860, 23283745, 22857948, 23782526). ClinVar contains an entry for this variant (Variation ID: 42913). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the affected amino acid(s) is currently unknown. This variant disrupts the p.Lys847 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 20031618, 22857948, 28615295, 23782526), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000168354 SCV000059453 likely pathogenic Hypertrophic cardiomyopathy 2018-07-10 criteria provided, single submitter clinical testing The p.Lys847del variant in MYH7 has been identified in at least 15 individuals w ith HCM and segregated with disease in at least 3 affected relatives (Van Driest 2004, Waldmuller 2008, Santos 2012, Kelly 2018, LMM data). This variant results in the deletion of a lysine (Lys) residue at position 847, but does not alter t he amino acid reading frame. In summary, although additional studies are require d to fully establish its clinical significance, the p.Lys847del variant is likel y pathogenic. ACMG/AMP Criteria applied: PS4, PM2, PP1, PM4_Supporting.
Laboratory of Genetics and Molecular Cardiology,University of São Paulo RCV000201461 SCV000256146 likely pathogenic Familial hypertrophic cardiomyopathy 1 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000223913 SCV000280326 likely pathogenic not provided 2012-01-16 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Lys847del (c.2539_2541delAAG). The variant has been seen in ~8 unrelated individuals with HCM (not including the patient's family) with weak segregation in an HCM kindred in our center (seen in three affected first degree relatives). Van Driest et al (2004) first reported the variant in one patient from the Mayo Clinic HCM cohort. Santos et al (2012) reported the variant in two unrelated patients from their Portuguese HCM cohort. Melissa at the Laboratory for Molecular Medicine told me that they have seen the variant in 4 additional unrelated families. These families have a range of ethnicities including Asian, Caucasian, mixed, and unknown. In one of those cases the proband carried another MYH7 variant in trans that the lab considered likely pathogenic. There is limited segregation data available, in one other family tested at the Laboratory for Molecular Medicine the variant is present in two affected family members. Waldmuller et al (2008) observed the variant in one patient with HCM. Other single amino acid deletions in MYH7 have been reported in association with HCM: p.Gly10del, p.Glu883del, p.Glu927del, p.Glu930del. Mutation Taster predicts the variant to be disease causing. Missense variants in neighboring codons have been reported in association with disease (p.Glu846Gln, p.Glu846Lys, p.Met852Thr). In total the variant has not been seen in ~7300 publicly available general population samples and published and laboratory controls.Van Driest et al (2004) did not observe the variant in 200 control individuals (100 Caucasians, 100 African-Americans). Santos et al (2012) did not observe the variant in 100 Portuguese control individuals. Familion reported that they did not see the variant in 400 controls of varying ancestries.The variant is not listed in dbSNP or 1000 genomes (which does include calls on deletions like this one; as of August 28th, 2012). Neither of those databases list in-frame amino acid deletions identified in control or general population samples. The NHLBI ESP recently released in-del data. As of February 20th, 2013 there are no in-dels reported in the exome variant server, which currently includes calls on ~6500 individuals.

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