NM_000257.4(MYH7):c.767G>A (p.Gly256Glu) AND Hypertrophic cardiomyopathy

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Dec 30, 2023
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:: RCV000693916.11

Allele description [Variation Report for NM_000257.4(MYH7):c.767G>A (p.Gly256Glu)]

NM_000257.4(MYH7):c.767G>A (p.Gly256Glu)

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.767G>A (p.Gly256Glu)

Other names:

p.G256E:GGA>GAA

HGVS:

NC_000014.9:g.23431447C>T
NG_007884.1:g.9215G>A
NM_000257.4:c.767G>AMANE SELECT
NP_000248.2:p.Gly256Glu
LRG_384t1:c.767G>A
LRG_384:g.9215G>A
NC_000014.8:g.23900656C>T
NM_000257.2:c.767G>A
NM_000257.3:c.767G>A
P12883:p.Gly256Glu
c.767G>A

Protein change:

G256E; GLY256GLU

Links:

UniProtKB: P12883#VAR_004570; OMIM: 160760.0012; dbSNP: rs121913633

NCBI 1000 Genomes Browser:

rs121913633

Molecular consequence:

NM_000257.4:c.767G>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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Fusinus longissimus voucher MNHN:IM:2007-32535 histone H3 gene, partial cds
Fusinus longissimus voucher MNHN:IM:2007-32535 histone H3 gene, partial cds
gi|1023301795|gb|KT754031.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000059654	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Jan 20, 2014)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 8483915, 12473556, 20031618, 9172070, 7731997, 8281650, 24033266
SCV000822339	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 30, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 8281650, 8483915, 18761664, 20031618, 31006259, 27532257, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000059654

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Pathogenic
(Jan 20, 2014)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV000822339

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 30, 2023)

germline

clinical testing

PubMed (7)
[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
not provided	germline	not provided	1	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

The in vitro motility activity of beta-cardiac myosin depends on the nature of the beta-myosin heavy chain gene mutation in hypertrophic cardiomyopathy.

Cuda G, Fananapazir L, Epstein ND, Sellers JR.

J Muscle Res Cell Motil. 1997 Jun;18(3):275-83.

PubMed [citation]

PMID:: 9172070

See all PubMed Citations (11)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000059654.6

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

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	not provided	not provided	not provided	not provided		1	not provided	1	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000822339.5

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

Description

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 256 of the MYH7 protein (p.Gly256Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 8281650, 8483915, 18761664, 20031618, 27532257, 31006259). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14099). 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: Sep 29, 2024

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