NM_000257.4(MYH7):c.1207C>T (p.Arg403Trp) AND Hypertrophic cardiomyopathy

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Dec 15, 2016
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000456661.18

Allele description [Variation Report for NM_000257.4(MYH7):c.1207C>T (p.Arg403Trp)]

NM_000257.4(MYH7):c.1207C>T (p.Arg403Trp)

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.1207C>T (p.Arg403Trp)

Other names:

p.R403W:CGG>TGG; NM_000257.3(MYH7):c.1207C>T

HGVS:

NC_000014.9:g.23429279G>A
NG_007884.1:g.11383C>T
NM_000257.4:c.1207C>TMANE SELECT
NP_000248.2:p.Arg403Trp
LRG_384t1:c.1207C>T
LRG_384:g.11383C>T
NC_000014.8:g.23898488G>A
NM_000257.2:c.1207C>T
NM_000257.3:c.1207C>T
P12883:p.Arg403Trp
c.1207C>T

Protein change:

R403W; ARG403TRP

Links:

UniProtKB: P12883#VAR_004575; OMIM: 160760.0015; dbSNP: rs3218714

NCBI 1000 Genomes Browser:

rs3218714

Molecular consequence:

NM_000257.4:c.1207C>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
SCV000059358	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Nov 11, 2020)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 8254035, 8268932, 10521296, 27532257, 15856146, 7662452, 30924982, 24033266
SCV000546195	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 28, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 8254035, 18029407, 10882745, 15010274, 1638703, 1975517, 12975413, 23751935, 28492532
SCV000564412	ClinGen Cardiomyopathy Variant Curation Expert Panel	reviewed by expert panel (ClinGen CMP ACMG Specifications v1)	Pathogenic (Dec 15, 2016)	germline	curation	PubMed (5) [See all records that cite these PMIDs] 8254035, 17612745, 27532257, 7662452, 29300372 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000059358

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Pathogenic
(Nov 11, 2020)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV000546195

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 28, 2023)

germline

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

SCV000564412

ClinGen Cardiomyopathy Variant Curation Expert Panel

reviewed by expert panel

(ClinGen CMP ACMG Specifications v1)

Pathogenic
(Dec 15, 2016)

germline

curation

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	6	4	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Identification of a new missense mutation at Arg403, a CpG mutation hotspot, in exon 13 of the beta-myosin heavy chain gene in hypertrophic cardiomyopathy.

Moolman JC, Brink PA, Corfield VA.

Hum Mol Genet. 1993 Oct;2(10):1731-2. No abstract available.

PubMed [citation]

PMID:: 8268932

The origins of hypertrophic cardiomyopathy-causing mutations in two South African subpopulations: a unique profile of both independent and founder events.

Moolman-Smook JC, De Lange WJ, Bruwer EC, Brink PA, Corfield VA.

Am J Hum Genet. 1999 Nov;65(5):1308-20.

PubMed [citation]

PMID:: 10521296
PMCID:: PMC1288283

See all PubMed Citations (18)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000059358.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	6	not provided	not provided	clinical testing	PubMed (8)

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		6	not provided	4	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000546195.10

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

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 403 of the MYH7 protein (p.Arg403Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial hypertrophic cardiomyopathy (PMID: 8254035, 18029407). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14102). 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%. Experimental studies have shown that this missense change affects MYH7 function (PMID: 10882745, 15010274). This variant disrupts the p.Arg403 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1638703, 1975517, 12975413, 23751935). 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 ClinGen Cardiomyopathy Variant Curation Expert Panel, SCV000564412.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (5)

Description

The c.1207C>T (p.Arg403Trp) variant in MYH7 has been reported in >20 individuals with hypertrophic cardiomyopathy and segregated with disease in >20 affected family members (PS4 and PP1_Strong; PMID:1052196; PMID:7662452; PMID:7848420; PMID:8254035; PMID:8268932; PMID:12707239; PMID:12974739; PMID:15010274; PMID:15856146; PMID:17612745; PMID:20428263; PMID:21239446; PMID:26383716; Partners LMM ClinVar SCV000059358.5; AGCMC Sydney ClinVar SCV000212643.1; SHaRe consortium, PMID: 30297972). This variant was absent from large population studies (PM2; http://exac.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). A different pathogenic missense variant has been previously identified at this codon which may indicate that this residue is critical to the function of the protein (PM5; c.1208G>A p.Arg403Gln - Variation ID 14087). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PP1_Strong; PM1; PM2; PM5; PP3

#	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

Last Updated: Oct 20, 2024

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