NM_000257.4(MYH7):c.2011C>T (p.Arg671Cys) AND Cardiomyopathy

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Sep 18, 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:: RCV000770495.6

Allele description [Variation Report for NM_000257.4(MYH7):c.2011C>T (p.Arg671Cys)]

NM_000257.4(MYH7):c.2011C>T (p.Arg671Cys)

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.2011C>T (p.Arg671Cys)

HGVS:

NC_000014.9:g.23426810G>A
NG_007884.1:g.13852C>T
NM_000257.4:c.2011C>TMANE SELECT
NP_000248.2:p.Arg671Cys
LRG_384t1:c.2011C>T
LRG_384:g.13852C>T
NC_000014.8:g.23896019G>A
NM_000257.2:c.2011C>T
NM_000257.3:c.2011C>T
P12883:p.Arg671Cys

Protein change:

R671C

Links:

UniProtKB: P12883#VAR_019857; dbSNP: rs727503263

NCBI 1000 Genomes Browser:

rs727503263

Molecular consequence:

NM_000257.4:c.2011C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cardiomyopathy (CMYO)
Synonyms:: Cardiomyopathies
Identifiers:: MONDO: MONDO:0004994; MedGen: C0878544; Human Phenotype Ontology: HP:0001638

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000901940	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario - Canadian Open Genetics Repository	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 18, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004100301	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Sep 5, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 12707239, 12820698, 25132132, 27532257, 32381727, 27885498 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000901940

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario - Canadian Open Genetics Repository

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Sep 18, 2024)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004100301

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Sep 5, 2023)

germline

clinical testing

PubMed (6)
[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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy.

Richard P, Charron P, Carrier L, Ledeuil C, Cheav T, Pichereau C, Benaiche A, Isnard R, Dubourg O, Burban M, Gueffet JP, Millaire A, Desnos M, Schwartz K, Hainque B, Komajda M; EUROGENE Heart Failure Project.

Circulation. 2003 May 6;107(17):2227-32. Epub 2003 Apr 21. Erratum in: Circulation. 2004 Jun 29;109(25):3258.

PubMed [citation]

PMID:: 12707239

See all PubMed Citations (7)

Details of each submission

From CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario - Canadian Open Genetics Repository, SCV000901940.2

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

Description

The c.2011C>T variant in MYH7 causes an amino acid substitution, which replaces arginine with cysteine at position 671. It has not been reported in control populations in the Genome Aggregation Database (gnomAD). It has been previously reported in at least 15 apparently unrelated individuals with hypertrophic cardiomyopathy (PMID 12707239, 12820698, 25132132, 27532257, 27885498, 34345284, 33769460, and others, ClinVar database; CHEO internal data). This variant was reported to segregate with disease in at least four families (PMID 27885498, 34345284, ClinVar database). It was also reported as de novo with unconfirmed parental relationship in an individual with cardiac hypertrophy (PMID 32381727). This variant is located within the head region (codons 181-937) of the Myosin-7 protein (NM_000257.2; NP_000248.2), where MYH7 pathogenic variants are significantly clustered (PMID 29300372). The Arg671 residue is highly conserved across evolutionarily distant species. In silico analysis programs (SIFT, PolyPhen-2, Mutation Taster) predict this variant to have an impact on the protein function. This variant is listed in ClinVar (VCV000164350). Based on the above information, we categorize this variant 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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004100301.1

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

Description

Variant summary: MYH7 c.2011C>T (p.Arg671Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 252082 control chromosomes. c.2011C>T has been reported in the literature in multiple individuals affected with Cardiomyopathy (e.g. Mohiddin_2003, Richard_2003, Wang_2014, Zhao_2021, Chida_2017, Walsh_2017). Additionally it was observed de novo patient (Zhao_2021) and in a family with Cardiomyopathy (Chida_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27885498, 12820698, 12707239, 27532257, 25132132, 32381727). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=1) and pathogenic/likely pathogenic (n=7). Based on the evidence outlined above, the variant was 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

Last Updated: Jan 13, 2025

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