NM_000257.4(MYH7):c.5135G>A (p.Arg1712Gln) AND Hypertrophic cardiomyopathy

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Dec 9, 2021
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:: RCV000199234.28

Allele description [Variation Report for NM_000257.4(MYH7):c.5135G>A (p.Arg1712Gln)]

NM_000257.4(MYH7):c.5135G>A (p.Arg1712Gln)

Genes:

LOC126861897:BRD4-independent group 4 enhancer GRCh37_chr14:23884455-23885654 [Gene]
MYH7:myosin heavy chain 7 [Gene - OMIM - HGNC]
MHRT:myosin heavy chain associated RNA transcript [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

14q11.2

Genomic location:

Preferred name:

NM_000257.4(MYH7):c.5135G>A (p.Arg1712Gln)

Other names:

p.R1712Q:CGG>CAG; NM_000257.3(MYH7):c.5135G>A; NM_000257.4(MYH7):c.5135G>A

HGVS:

NC_000014.9:g.23415651C>T
NG_007884.1:g.25011G>A
NM_000257.4:c.5135G>AMANE SELECT
NP_000248.2:p.Arg1712Gln
LRG_384t1:c.5135G>A
LRG_384:g.25011G>A
NC_000014.8:g.23884860C>T
NM_000257.2:c.5135G>A
NM_000257.3:c.5135G>A
NR_126491.1:n.83C>T
c.5135G>A

Protein change:

R1712Q

Links:

dbSNP: rs193922390

NCBI 1000 Genomes Browser:

rs193922390

Molecular consequence:

NM_000257.4:c.5135G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_126491.1:n.83C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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
SCV000059603	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 19, 2022)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 15483641, 18403758, 21511876, 24510615, 23785128, 23074333, 27532257, 27247418, 24498601, 23197161, 25741868
SCV000253686	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 25, 2023)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 18403758, 21511876, 23785128, 24510615, 27247418, 27532257, 31308319, 32894683, 15483641, 28492532
SCV000564455	ClinGen Cardiomyopathy Variant Curation Expert Panel	reviewed by expert panel (ClinGen CMP ACMG Specifications v1)	Pathogenic (Dec 9, 2021)	germline	curation	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000747336	Centre for Mendelian Genomics, University Medical Centre Ljubljana	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 1, 2017)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000804895	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	no assertion criteria provided	Likely pathogenic (Nov 29, 2016)	germline	clinical testing
SCV005430777	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 28, 2024)	germline	clinical testing	PubMed (17) [See all records that cite these PMIDs] 18403758, 21511876, 23785128, 24510615, 27247418, 27532257, 28771489, 30297972, 31308319, 33495596, 33495597, 34352619, 34542152, 35026164, 35176171, 37488328, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	8	not provided	not provided	143475	not provided	clinical testing, curation
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Cardiac structural and sarcomere genes associated with cardiomyopathy exhibit marked intolerance of genetic variation.

Pan S, Caleshu CA, Dunn KE, Foti MJ, Moran MK, Soyinka O, Ashley EA.

Circ Cardiovasc Genet. 2012 Dec;5(6):602-10. doi: 10.1161/CIRCGENETICS.112.963421. Epub 2012 Oct 16.

PubMed [citation]

PMID:: 23074333
PMCID:: PMC3526690

MT-CYB mutations in hypertrophic cardiomyopathy.

Hagen CM, Aidt FH, Havndrup O, Hedley PL, Jespersgaard C, Jensen M, Kanters JK, Moolman-Smook JC, Møller DV, Bundgaard H, Christiansen M.

Mol Genet Genomic Med. 2013 May;1(1):54-65. doi: 10.1002/mgg3.5. Epub 2013 Apr 12. Erratum in: Mol Genet Genomic Med. 2013 Sep;1(3):187.

PubMed [citation]

PMID:: 24498601
PMCID:: PMC3893158

See all PubMed Citations (24)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000059603.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

The p.Arg1712Gln variant in MYH7 has been reported in more than 15 individuals with hypertrophic cardiomyopathy (HCM; Morita 2008 PMID: 18403758, Gruner 2011 PMID: 21511876, Mook 2013 PMID: 23785128, Walsh 2016 PMID: 27532257, LMM data), including at least 1 individual with a likely disease-causing variant in another gene. This variant did not segregate with disease in one affected family member from one family (Mook 2013 PMID: 23785128), but did segregate in more than 15 affected individuals with HCM in at least 9 families (LMM internal data, GeneDx personal communication, Mayo Personal Communication, OMGL personal communication). This variant has been identified in 0.0045 (3/68048) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org, v.3.1.2). This variant has been classified as pathogenic on December 9, 2021 by the ClinGen Cardiomyopathy Variant Curation Expert Panel (Variation ID 36642). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. Criteria applied (Richards 2015): PS4, PP1_Strong, PM2_Supporting.

#	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, SCV000253686.12

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1712 of the MYH7 protein (p.Arg1712Gln). This variant is present in population databases (rs193922390, gnomAD 0.005%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 18403758, 21511876, 23785128, 24510615, 27247418, 27532257, 31308319, 32894683). ClinVar contains an entry for this variant (Variation ID: 36642). 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.Arg1712 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15483641). 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, SCV000564455.5

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

Description

The NM_000257.4(MYH7):c.5135G>A (p.Arg1712Gln) variant has been reported in >30 individuals with HCM (PS4; Miller 2013 PMID: 23054336; Mook 2013 PMID: 23785128; Glotov 2015 PMID: 25892673; Lopes 2015 PMID: 25351510; Helms 2016 PMID: 27688314; Mademont-Soler 2017 PMID: 28771489; Weissler-Snir 2017 PMID: 28193612; van Velzen 2017 PMID: 2879411; van Lint 2019 PMID: 30847666; Tran Vu 2019 PMID: 31308319; Ambry pers. comm.; CHEO pers. comm.; GeneDx pers. comm.; LMM pers. comm.; Mayo pers. comm.; OMGL pers. comm.). This variant segregated with disease in >15 affected relatives with HCM in at least 9 families (PP1_strong; GeneDx pers. comm.; LMM pers. comm.; OMGL pers. comm.). This variant has also been identified in 0.002% (FAF 95% CI; 6/128842) of European chromosomes by gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. 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, PM2.

#	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 Centre for Mendelian Genomics, University Medical Centre Ljubljana, SCV000747336.1

#	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	unknown	yes	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, SCV000804895.1

#	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 All of Us Research Program, National Institutes of Health, SCV005430777.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	8	not provided	not provided	clinical testing	PubMed (17)

Description

This missense variant replaces arginine with glutamine at codon 1712 in the LMM domain of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 30 individuals affected with hypertrophic cardiomyopathy (PMID: 18403758, 21511876, 23785128, 24510615, 27247418, 27532257, 28771489, 30297972, 31308319, 33495596, 33495597, 34352619, 34542152, 35026164, 35176171). It has been shown that this variant segregates with disease in over 20 affected relatives across at least 10 families (PMID: 37488328; ClinVar SCV000564455.5). This variant has been shown to have both age- and sex-dependent penetrance (PMID: 37488328). This variant has been identified in 6/282354 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg1712Trp, is considered to be disease-causing (Clinvar variation ID: 14118), indicating that arginine at this position is important for MYH7 protein function. Based on the available evidence, this variant is classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	143475	not provided	not provided		8	not provided	not provided	not provided

Last Updated: Jan 13, 2025

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