dbSNP rs397516155: MYH7:p.Lys847del (chr14-23424906-CCTT-C) – ACMG Classification: Likely_pathogenic (8 pts)

Genes affected

MYH7 (HGNC:7577): (myosin heavy chain 7) Muscle myosin is a hexameric protein containing 2 heavy chain subunits, 2 alkali light chain subunits, and 2 regulatory light chain subunits. This gene encodes the beta (or slow) heavy chain subunit of cardiac myosin. It is expressed predominantly in normal human ventricle. It is also expressed in skeletal muscle tissues rich in slow-twitch type I muscle fibers. Changes in the relative abundance of this protein and the alpha (or fast) heavy subunit of cardiac myosin correlate with the contractile velocity of cardiac muscle. Its expression is also altered during thyroid hormone depletion and hemodynamic overloading. Mutations in this gene are associated with familial hypertrophic cardiomyopathy, myosin storage myopathy, dilated cardiomyopathy, and Laing distal myopathy. [provided by RefSeq, May 2022]

MYH7 links:

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PM4

For more information check the summary or visit ClinGen Evidence Repository.

PP1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH7	NM_000257.4 link	c.2539_2541delAAG	p.Lys847del	conservative_inframe_deletion	Exon 22 of 40	ENST00000355349.4	NP_000248.2	P12883
MYH7	NM_001407004.1 link	c.2539_2541delAAG	p.Lys847del	conservative_inframe_deletion	Exon 21 of 39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4 link	c.2539_2541delAAG	p.Lys847del	conservative_inframe_deletion	Exon 22 of 40	1	NM_000257.4	ENSP00000347507.3		P12883

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461894

Hom.:

AF XY:

0.00

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:13

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy

Pathogenic:5

Feb 20, 2019

Center of Genomic medicine, Geneva, University Hospital of Geneva

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 05, 2021

ClinGen Cardiomyopathy Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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. -

Jul 10, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Dec 15, 2023

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

not provided

Pathogenic:3

Jan 16, 2012

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: 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. -

Oct 16, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

May 20, 2020

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy 1

Pathogenic:2

May 02, 2018

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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'. -

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dilated cardiomyopathy 1S

Pathogenic:1

Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Primary familial hypertrophic cardiomyopathy

Pathogenic:1

Sep 01, 2014

Blueprint Genetics

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiovascular phenotype

Pathogenic:1

Jul 02, 2020

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

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Splicing

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SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

rs397516155

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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