NM_000257.4(MYH7):c.1987C>T (p.Arg663Cys) AND Hypertrophic cardiomyopathy

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Jan 29, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000459608.17

Allele description [Variation Report for NM_000257.4(MYH7):c.1987C>T (p.Arg663Cys)]

NM_000257.4(MYH7):c.1987C>T (p.Arg663Cys)

Gene:

MYH7:myosin heavy chain 7 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

14q11.2

Genomic location:

Preferred name:

NM_000257.4(MYH7):c.1987C>T (p.Arg663Cys)

Other names:

p.R663C:CGC>TGC

HGVS:

NC_000014.9:g.23426834G>A
NG_007884.1:g.13828C>T
NM_000257.4:c.1987C>TMANE SELECT
NP_000248.2:p.Arg663Cys
LRG_384t1:c.1987C>T
LRG_384:g.13828C>T
NC_000014.8:g.23896043G>A
NM_000257.2:c.1987C>T
NM_000257.3:c.1987C>T
P12883:p.Arg663Cys
c.1987C>T

Protein change:

R663C

Links:

UniProtKB: P12883#VAR_042798; dbSNP: rs397516127

NCBI 1000 Genomes Browser:

rs397516127

Molecular consequence:

NM_000257.4:c.1987C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Hypertrophic cardiomyopathy
Synonyms:: HYPERTROPHIC MYOCARDIOPATHY
Identifiers:: MONDO: MONDO:0005045; MeSH: D002312; MedGen: C0007194; Human Phenotype Ontology: HP:0001639

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000059408	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Jun 26, 2019)	germline	clinical testing	PubMed (17) [See all records that cite these PMIDs] 25524337, 23674513, 23283745, 10750581, 23290139, 23785128, 23233322, 12707239, 18533079, 27082122, 25714468, 15563892, 15358028, 15858117, 18383048, 20350521, 24033266
SCV000546267	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 29, 2024)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 15358028, 15563892, 15858117, 18383048, 20800588, 22112859, 23233322, 23283745, 23690394, 10750581, 11133230, 28492532
SCV004175575	Genetics and Molecular Pathology, SA Pathology See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 16, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 15358028, 15563892, 30775854, 32344918, 32894683, 33673806, 35626289, 25741868
SCV004844789	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Oct 30, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 15358028, 15563892, 15858117, 18533079, 20350521, 23674513, 27532257, 31568572, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	21	10	not provided	108544	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Clinical phenotype and outcome of hypertrophic cardiomyopathy associated with thin-filament gene mutations.

Coppini R, Ho CY, Ashley E, Day S, Ferrantini C, Girolami F, Tomberli B, Bardi S, Torricelli F, Cecchi F, Mugelli A, Poggesi C, Tardiff J, Olivotto I.

J Am Coll Cardiol. 2014 Dec 23;64(24):2589-2600. doi: 10.1016/j.jacc.2014.09.059.

PubMed [citation]

PMID:: 25524337
PMCID:: PMC4270453

Abnormal calcium handling properties underlie familial hypertrophic cardiomyopathy pathology in patient-specific induced pluripotent stem cells.

Lan F, Lee AS, Liang P, Sanchez-Freire V, Nguyen PK, Wang L, Han L, Yen M, Wang Y, Sun N, Abilez OJ, Hu S, Ebert AD, Navarrete EG, Simmons CS, Wheeler M, Pruitt B, Lewis R, Yamaguchi Y, Ashley EA, Bers DM, Robbins RC, et al.

Cell Stem Cell. 2013 Jan 3;12(1):101-13. doi: 10.1016/j.stem.2012.10.010.

PubMed [citation]

PMID:: 23290139
PMCID:: PMC3638033

See all PubMed Citations (30)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000059408.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	20	not provided	not provided	clinical testing	PubMed (17)

Description

proposed classification - variant undergoing re-assessment, contact laboratory

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		20	not provided	10	not provided

From Invitae, SCV000546267.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 663 of the MYH7 protein (p.Arg663Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (HCM) (PMID: 15358028, 15563892, 15858117, 18383048, 20800588, 22112859, 23233322, 23283745, 23690394). ClinVar contains an entry for this variant (Variation ID: 42874). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg663 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10750581, 11133230). 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genetics and Molecular Pathology, SA Pathology, SCV004175575.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

The MYH7 c.1987C>T variant is classified as Pathogenic (PS4, PM1, PM2, PP1_Moderate, PP3.) The MYH7 c.1987C>T variant is a single nucleotide change in exon 18/40 of the MYH7 gene, which is predicted to change the amino acid arginine at position 663 in the protein, to cysteine. This amino acid is within the conserved functional domain of the MYH7 protein where variation is expected to be disease causing (PM1). The variant has been reported in excess of 20 probands with a clinical presentation of Hypertrophic Cardiomyopathy (PMID#15358028, 33673806, 32344918, 30775854, 32894683, 35626289) (PS4) and is absent from population databases (PM2). This variant has been reported to segregate with disease (PMID #15563892, our cohort and SHaRE) (PP1_moderate). Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs397516127) is reported as disease causing in the HGMD database (CM973126) and is reported as pathogenic by multiple other diagnostic laboratories (ClinVar #42874).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004844789.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (9)

Description

This missense variant replaces arginine with cysteine at codon 663 in the myosin head/motor (S1) domain of the MYH7 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant is found within a highly conserved region of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in more than 15 unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 15358028, 15563892, 15858117, 18533079, 20350521, 23674513, 27532257, 31568572). A different variant occurring at the same codon, p.Arg663His, is a well documented pathogenic mutation (Clinvar variation ID: 42875), indicating that arginine at this position is important for MYH7 protein function. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Apr 20, 2024

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