NM_000257.4(MYH7):c.1750G>C (p.Gly584Arg) 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:: RCV000471604.16

Allele description [Variation Report for NM_000257.4(MYH7):c.1750G>C (p.Gly584Arg)]

NM_000257.4(MYH7):c.1750G>C (p.Gly584Arg)

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.1750G>C (p.Gly584Arg)

Other names:

p.G584R:GGC>CGC; NM_000257.3(MYH7):c.1750G>C

HGVS:

NC_000014.9:g.23427723C>G
NG_007884.1:g.12939G>C
NM_000257.4:c.1750G>CMANE SELECT
NP_000248.2:p.Gly584Arg
LRG_384t1:c.1750G>C
LRG_384:g.12939G>C
NC_000014.8:g.23896932C>G
NM_000257.2:c.1750G>C
NM_000257.3:c.1750G>C
P12883:p.Gly584Arg
c.1750G>C

Protein change:

G584R; GLY584ARG

Links:

UniProtKB: P12883#VAR_004578; OMIM: 160760.0004; dbSNP: rs121913626

NCBI 1000 Genomes Browser:

rs121913626

Molecular consequence:

NM_000257.4:c.1750G>C - 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
SCV000059395	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Feb 19, 2021)	germline	clinical testing	PubMed (14) [See all records that cite these PMIDs] 1552912, 8250038, 8335820, 22429680, 21769673, 7731997, 9062359, 10567705, 23408646, 24093860, 27247418, 27532257, 12953063, 24033266
SCV000546174	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 17, 2024)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 8250038, 22429680, 24093860, 12953063, 12974739, 23283745, 24510615, 26187847, 28492532
SCV000564418	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] 1552912, 27532257, 10567705, 24093860, 29300372 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000059395

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Pathogenic
(Feb 19, 2021)

germline

clinical testing

PubMed (14)
[See all records that cite these PMIDs]

SCV000546174

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 17, 2024)

germline

clinical testing

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

SCV000564418

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	33	28	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Left ventricular hypertrophy and morphology in familial hypertrophic cardiomyopathy associated with mutations of the beta-myosin heavy chain gene.

Solomon SD, Wolff S, Watkins H, Ridker PM, Come P, McKenna WJ, Seidman CE, Lee RT.

J Am Coll Cardiol. 1993 Aug;22(2):498-505.

PubMed [citation]

PMID:: 8335820

Unequal allelic expression of wild-type and mutated β-myosin in familial hypertrophic cardiomyopathy.

Tripathi S, Schultz I, Becker E, Montag J, Borchert B, Francino A, Navarro-Lopez F, Perrot A, Özcelik C, Osterziel KJ, McKenna WJ, Brenner B, Kraft T.

Basic Res Cardiol. 2011 Nov;106(6):1041-55. doi: 10.1007/s00395-011-0205-9. Epub 2011 Jul 19.

PubMed [citation]

PMID:: 21769673
PMCID:: PMC3228959

See all PubMed Citations (20)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000059395.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	33	not provided	not provided	clinical testing	PubMed (14)

Description

The p.Gly584Arg variant in MYH7 has been reported in at least 8 individuals with HCM (Watkins 1993 PMID:8250038, Nier 1999 PMID:10567705, Santos 2012 PMID: 22429680, Marsiglia 2013 PMID:24093860) and has been identified by our laboratory in >20 individuals with HCM. Furthermore, this variant segregated with disease in 5 affected members (including 1 obligate carrier) from 4 families (Watkins 1993 PMID:8250038, LMM data). It has also been identified in 0.001% (1/113768) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant lies in the head region of the protein and missense variants in this region are statistically more likely to be disease-associated (Walsh 2017 PMID:27532257). In vitro functional studies support an impact on protein function (Fujita 1998 PMID:9062359, Wang 2003 PMID:12953063) and computational prediction tools and conservation analyses are consistent with pathogenicity. Additionally, this variant was classified as pathogenic on 12/15/2016 by the ClinGen-approved Cardiomyopathy expert panel (Variation ID 14090). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP criteria applied: PS4, PP1_Moderate, PM2_supporting, PM1, PS3_Supporting, 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		33	not provided	28	not provided

From Invitae, SCV000546174.10

#	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 glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 584 of the MYH7 protein (p.Gly584Arg). This variant is present in population databases (rs121913626, gnomAD 0.0009%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 8250038, 22429680, 24093860). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14090). 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: 12953063). This variant disrupts the p.Gly584 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12974739, 23283745, 24510615, 26187847). 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, SCV000564418.5

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

Description

The c.1750G>C (p.Gly584Arg) variant in MYH7 has been reported in >25 individuals with hypertrophic cardiomyopathy (PS4; PMID:1552912; PMID:10567705; PMID:24093860; Partners LMM ClinVar SCV000059395.5; SHaRe consortium, PMID: 30297972). This variant segregated with disease in >5 affected individuals (PP1_Moderate; PMID:1552912; Partners LMM ClinVar SCV000059395.5). 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). 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; PM1; PM2; PP1_Moderate; 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: May 1, 2024

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