ClinVar Genomic variation as it relates to human health

The NM_000257.4: c.2539_2541del (p.Lys847del) variant in MYH7 has been reported in >15 individuals with HCM (PS4; Van Driest 2004 PMID:15358028; Santos 2012 PMID:22429680; Kassem 2013 PMID:23233322; Marsiglia 2013 PMID:24093860; Waldmuller 2008 PMID:18258667; Walsh 2017 PMID: 27532257; Ho 2018 PMID: 30297972; Jaaskelainen 2019 PMID: 30775854; LMM pers. comm.; Invitae pers. comm.). This variant segregated with disease in 3 affected individuals with HCM from 2 families(PP1; LMM pers. comm.). This variant was absent from large population studies (PM2; gnomAD v.2.1.1, 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. Given that only 1 amino acid has been deleted, the expert panel felt that adjusting to supporting evidence would be more appropriate in this case (PM4_Supporting). 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 (Kelly 2018 PMID:29300372): PS4; PP1; PM2; PM4_Supporting.

This variant was identified in a patient with familial hypertrophic cardiomyopathy, in combination with one variant in VCL and one variant in MYPN. The affected mother and affected brother of the patient also harbour this variant.

This variant, c.2539_2541del, 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 (gnomAD no frequency). This variant has been observed in individuals with hypertrophic cardiomyopathy (PMID: 15358028, 22429680, 22857948, 23233322, 23283745, 23782526, 24093860). ClinVar contains an entry for this variant (Variation ID: 42913). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant disrupts the p.Lys847 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20031618, 22857948, 23782526, 28615295). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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.

MYH7 Lys847del has been previously reported in more than 10 HCM probands (Walsh R, et al., 2017; Kapplinger JD, et al., 2014; Kassem HSh, et al., 2013; Marsiglia JD, et al., 2013; Santos S, et al., 2012; Waldmuller S, et al., 2008; Van Driest SL, et al., 2004) and has been reported to segregate with disease in at least 2 families (Stanford, ClinVar:SCV000280326.1; LMM, ClinVar:SCV000059453.4). The variant is absent in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). We identified this variant in a HCM proband with no family history of disease. Based on the adapted ACMG criteria (Kelly MA, et al., 2018) this variant has been reported in more than 10 unrelated probands (PS4), is rare in the general population (PM2), causes a truncated protein (PM4) and segregated to other affected family members (PP1), therefore we classify MYH7 Lys847del as 'likely pathogenic'.

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15358028, 22857948, 22429680, 23549607, 25892673, 27483260, 18258667, 24510615, 23233322, 24093860, 27532257, 28214152, 23782526, 36243179, 32894683, 29300372, 23283745, 33673806, 30775854)

This variant is predicted to result in an in-frame deletion of one amino acid. This variant has been reported in multiple individuals with hypertrophic cardiomyopathy (PMID: 15358028, 22429680, 23233322, 24093860, 18258667, 27532257, 30297972, 30775854). This variant is absent from or rare in large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant has been reported to co-segregate with disease in 3 affected individuals in two families (communication with laboratory).

The c.2539_2541del variant (also known as p.K847del) is located in coding exon 20 of the MYH7 gene. This variant results from an in-frame AAG deletion at nucleotide positions 2539 to 2541. This results in the in-frame deletion of a lysine residue at codon 847 in the head domain of the MYH7 protein. This alteration has been detected in numerous individuals with hypertrophic cardiomyopathy, and it has been reported to segregate with disease in a few affected relatives (Van Driest SL et al. J. Am. Coll. Cardiol., 2004 Aug;44:602-10; Santos S et al. BMC Med. Genet., 2012 Mar;13:17; Kassem HSh et al. J Cardiovasc Transl Res, 2013 Feb;6:65-80; Marsiglia JD et al. Am. Heart J., 2013 Oct;166:775-82; Núñez L et al. Circ. J., 2013 Jun;77:2358-65; Zou Y et al. Mol. Biol. Rep., 2013 Jun;40:3969-76; Rubattu S et al. Int J Mol Sci, 2016 Jul;17:; Walsh R et al. Genet. Med., 2017 02;19:192-203; Ho CY et al. Circulation, 2018 10;138:1387-1398; Kelly MA et al. Genet. Med., 2018 03;20:351-359; Jääskeläinen P et al. ESC Heart Fail, 2019 Apr;6:436-445). In addition, this amino acid position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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.