NM_000257.4(MYH7):c.2156G>A (p.Arg719Gln) AND Hypertrophic cardiomyopathy

Germline classification:: Pathogenic (5 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:: RCV000468000.19

Allele description [Variation Report for NM_000257.4(MYH7):c.2156G>A (p.Arg719Gln)]

NM_000257.4(MYH7):c.2156G>A (p.Arg719Gln)

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.2156G>A (p.Arg719Gln)

Other names:

p.R719Q:CGG>CAG; NM_000257.3(MYH7):c.2156G>A

HGVS:

NC_000014.9:g.23425970C>T
NG_007884.1:g.14692G>A
NM_000257.4:c.2156G>AMANE SELECT
NP_000248.2:p.Arg719Gln
LRG_384t1:c.2156G>A
LRG_384:g.14692G>A
NC_000014.8:g.23895179C>T
NM_000257.2:c.2156G>A
NM_000257.3:c.2156G>A
P12883:p.Arg719Gln
c.2156G>A

Protein change:

R719Q; ARG719GLN

Links:

UniProtKB: P12883#VAR_017749; OMIM: 160760.0021; dbSNP: rs121913641

NCBI 1000 Genomes Browser:

rs121913641

Molecular consequence:

NM_000257.4:c.2156G>A - 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
SCV000059421	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 21, 2023)	germline	clinical testing	PubMed (20) [See all records that cite these PMIDs] 7848441, 10521296, 16199542, 12473556, 15358028, 11498078, 12707239, 18409188, 20800588, 18411228, 20309391, 23711808, 23140321, 21310275, 24510615, 27532257, 21896538, 27483260, 24093860, 25741868
SCV000546248	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 20, 2024)	germline	clinical testing	PubMed (14) [See all records that cite these PMIDs] 7848441, 15358028, 15519027, 15858117, 16199542, 18409188, 21896538, 23140321, 23711808, 10882745, 8282798, 20811150, 21310275, 28492532
SCV000564422	ClinGen Cardiomyopathy Variant Curation Expert Panel	reviewed by expert panel (ClinGen CMP ACMG Specifications v1)	Pathogenic (Dec 15, 2016)	germline	curation	PubMed (7) [See all records that cite these PMIDs] 16199542, 15358028, 7848441, 15858117, 27532257, 18411228, 29300372 Citation Link,
SCV000804892	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	no assertion criteria provided	Likely pathogenic (Mar 3, 2016)	germline	clinical testing
SCV000886786	Center for Human Genetics, University of Leuven	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 31, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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, curation
not provided	germline	yes	not provided	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Prevalence and severity of "benign" mutations in the beta-myosin heavy chain, cardiac troponin T, and alpha-tropomyosin genes in hypertrophic cardiomyopathy.

Van Driest SL, Ackerman MJ, Ommen SR, Shakur R, Will ML, Nishimura RA, Tajik AJ, Gersh BJ.

Circulation. 2002 Dec 10;106(24):3085-90.

PubMed [citation]

PMID:: 12473556

See all PubMed Citations (27)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000059421.7

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

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		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000546248.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (14)

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 719 of the MYH7 protein (p.Arg719Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (HCM) (PMID: 7848441, 15358028, 15519027, 15858117, 16199542, 18409188, 21896538, 23140321, 23711808). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14107). 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). This variant disrupts the p.Arg719 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8282798, 20811150, 21310275). 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, SCV000564422.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (7)

Description

The c.2156G>A (p.Arg719Gln) variant in MYH7 has been reported in >30 individuals with hypertrophic cardiomyopathy (PS4; PMID:7848441; PMID:16199542; PMID:15358028; PMID:18411228; Partners LMM ClinVar SCV000059421.5; AGCMC Sydney ClinVar SCV000212634.1; SHaRe consortium, PMID: 30297972). This variant segregated with disease in 7 affected individuals (PP1_Strong; PMID:7848441; Partners LMM ClinVar SCV000059421.5). 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.2155C>T p.Arg719Trp ClinVar Variation ID 14104). 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

From Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital, SCV000804892.1

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

#	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 Center for Human Genetics, University of Leuven, SCV000886786.1

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

#	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	1	not provided

Last Updated: Sep 29, 2024

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