NM_000257.4(MYH7):c.2302G>A (p.Gly768Arg) AND Hypertrophic cardiomyopathy

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 9, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000462424.12

Allele description [Variation Report for NM_000257.4(MYH7):c.2302G>A (p.Gly768Arg)]

NM_000257.4(MYH7):c.2302G>A (p.Gly768Arg)

Genes:

LOC126861898:BRD4-independent group 4 enhancer GRCh37_chr14:23893609-23894808 [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.2302G>A (p.Gly768Arg)

Other names:

p.G768R:GGG>AGG

HGVS:

NC_000014.9:g.23425403C>T
NG_007884.1:g.15259G>A
NM_000257.4:c.2302G>AMANE SELECT
NP_000248.2:p.Gly768Arg
LRG_384t1:c.2302G>A
LRG_384:g.15259G>A
NC_000014.8:g.23894612C>T
NM_000257.2:c.2302G>A
NM_000257.3:c.2302G>A
P12883:p.Gly768Arg

Protein change:

G768R

Links:

UniProtKB: P12883#VAR_019859; dbSNP: rs727503260

NCBI 1000 Genomes Browser:

rs727503260

Molecular consequence:

NM_000257.4:c.2302G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000546207	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 9, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 12707239, 18076673, 20394946, 20800588, 22260945, 25935763, 27532257, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000546207

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 9, 2023)

germline

clinical testing

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

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

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

Pediatric restrictive cardiomyopathy associated with a mutation in beta-myosin heavy chain.

Ware SM, Quinn ME, Ballard ET, Miller E, Uzark K, Spicer RL.

Clin Genet. 2008 Feb;73(2):165-70. Epub 2007 Dec 12.

PubMed [citation]

PMID:: 18076673

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000546207.10

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

Description

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 768 of the MYH7 protein (p.Gly768Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (HCM) and restrictive cardiomyopathy (RCM) (PMID: 12707239, 18076673, 20394946, 20800588, 22260945, 25935763; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 164337). 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 is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). 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

Last Updated: Oct 20, 2024

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