NM_000257.4(MYH7):c.2717A>G (p.Asp906Gly) 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:: RCV000469895.16

Allele description [Variation Report for NM_000257.4(MYH7):c.2717A>G (p.Asp906Gly)]

NM_000257.4(MYH7):c.2717A>G (p.Asp906Gly)

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.2717A>G (p.Asp906Gly)

Other names:

NM_000257.3(MYH7):c.2717A>G

HGVS:

NC_000014.9:g.23424112T>C
NG_007884.1:g.16550A>G
NM_000257.4:c.2717A>GMANE SELECT
NP_000248.2:p.Asp906Gly
LRG_384t1:c.2717A>G
LRG_384:g.16550A>G
NC_000014.8:g.23893321T>C
NM_000257.2:c.2717A>G
NM_000257.3:c.2717A>G
P12883:p.Asp906Gly
c.2717A>G

Protein change:

D906G; ASP906GLY

Links:

UniProtKB: P12883#VAR_042814; OMIM: 160760.0039; dbSNP: rs267606908

NCBI 1000 Genomes Browser:

rs267606908

Molecular consequence:

NM_000257.4:c.2717A>G - 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
SCV000059468	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 5, 2019)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 15528230, 16267253, 12081993, 21310275, 24510615, 25741868
SCV000546214	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 10, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 12081993, 24510615, 24704860, 15528230, 28492532
SCV000564437	ClinGen Cardiomyopathy Variant Curation Expert Panel	reviewed by expert panel (ClinGen CMP ACMG Specifications v1)	Pathogenic (Dec 15, 2016)	germline	curation	PubMed (6) [See all records that cite these PMIDs] 15528230, 24510615, 16267253, 12081993, 27532257, 29300372 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000059468

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Apr 5, 2019)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV000546214

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 10, 2024)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV000564437

ClinGen Cardiomyopathy Variant Curation Expert Panel

reviewed by expert panel

(ClinGen CMP ACMG Specifications v1)

Pathogenic
(Dec 15, 2016)

germline

curation

PubMed (6)
[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	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Development and validation of a computational method for assessment of missense variants in hypertrophic cardiomyopathy.

Jordan DM, Kiezun A, Baxter SM, Agarwala V, Green RC, Murray MF, Pugh T, Lebo MS, Rehm HL, Funke BH, Sunyaev SR.

Am J Hum Genet. 2011 Feb 11;88(2):183-92. doi: 10.1016/j.ajhg.2011.01.011.

PubMed [citation]

PMID:: 21310275
PMCID:: PMC3035712

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

See all PubMed Citations (10)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000059468.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

The p.Asp906Gly variant in MYH7 has been identified in >15 individuals with HCM and segregated with disease in >10 affected relatives from 2 families, although reduced penetrance was noted in both families (Ho 2002, Alpert 2005, Arad 2005, Kapplinger 2014, LMM data). It has been identified in 1/246244 of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs267606908). This low frequency is consistent with the prevalence and penetrance of the condition in the general population. In vitro functional studies provide some evidence that the p.Asp906Gly variant may impact protein function (Alpert 2005). In addition, the p.Asp906Gly variant was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, this variant meets criteria to be classified as pathogenic for HCM in an autosomal dominant manner based upon segregation studies, low frequency in the general population and functional evidence. The ACMG/AMP criteria applied: PS4, PM2, PP1_Strong, 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000546214.10

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

Description

This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 906 of the MYH7 protein (p.Asp906Gly). This variant is present in population databases (rs267606908, gnomAD 0.0009%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (HCM) (PMID: 12081993, 15528230, 24510615, 24704860). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14125). 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: 15528230). 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, SCV000564437.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (6)

Description

The c.2717A>G (p.Asp906Gly) variant in MYH7 has been reported in >20 individuals with hypertrophic cardiomyopathy (PS4; PMID:27532257; PMID:12081993; PMID:15528230; PMID:16267253; PMID:24510615; Partners LMM ClinVar SCV000059468.5). This variant segregated with disease in 10 affected individuals (PP1_Strong; PMID:12081993; PMID:15528230). 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). 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

#	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: Nov 3, 2024

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