NM_000257.4(MYH7):c.1231G>A (p.Val411Ile) AND Hypertrophic cardiomyopathy

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Nov 28, 2024
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:: RCV000697577.10

Allele description [Variation Report for NM_000257.4(MYH7):c.1231G>A (p.Val411Ile)]

NM_000257.4(MYH7):c.1231G>A (p.Val411Ile)

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.1231G>A (p.Val411Ile)

Other names:

p.V411I:GTC>ATC

HGVS:

NC_000014.9:g.23429255C>T
NG_007884.1:g.11407G>A
NM_000257.4:c.1231G>AMANE SELECT
NP_000248.2:p.Val411Ile
LRG_384t1:c.1231G>A
LRG_384:g.11407G>A
NC_000014.8:g.23898464C>T
NM_000257.2:c.1231G>A
NM_000257.3:c.1231G>A
P12883:p.Val411Ile

Protein change:

V411I

Links:

UniProtKB: P12883#VAR_029432; dbSNP: rs730880868

NCBI 1000 Genomes Browser:

rs730880868

Molecular consequence:

NM_000257.4:c.1231G>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000826197	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 28, 2024)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 12974739, 12975413, 20800588, 22429680, 23785128, 27532257, 29121657, 30847666, 32894683, 28492532
SCV004830240	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Aug 17, 2023)	germline	clinical testing	PubMed (17) [See all records that cite these PMIDs] 12974739, 12975413, 15858117, 20624503, 20800588, 22429680, 23140321, 23785128, 25351510, 27532257, 29121657, 30847666, 32481709, 32731933, 32894683, 33495597, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000826197

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 28, 2024)

germline

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

SCV004830240

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(Aug 17, 2023)

germline

clinical testing

PubMed (17)
[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	2	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9..

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Mutation spectrum in a large cohort of unrelated consecutive patients with hypertrophic cardiomyopathy.

Erdmann J, Daehmlow S, Wischke S, Senyuva M, Werner U, Raible J, Tanis N, Dyachenko S, Hummel M, Hetzer R, Regitz-Zagrosek V.

Clin Genet. 2003 Oct;64(4):339-49.

PubMed [citation]

PMID:: 12974739

See all PubMed Citations (18)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000826197.7

#	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 valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 411 of the MYH7 protein (p.Val411Ile). This variant is present in population databases (rs730880868, gnomAD 0.006%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12974739, 12975413, 20800588, 22429680, 23785128, 27532257, 29121657, 30847666, 32894683). ClinVar contains an entry for this variant (Variation ID: 181339). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. 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 All of Us Research Program, National Institutes of Health, SCV004830240.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (17)

Description

This missense variant replaces valine with isoleucine at codon 411 of the MYH7 protein. This variant is found within a highly conserved region of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 15 individuals affected with hypertrophic cardiomyopathy (PMID: 12974739, 12975413, 20624503, 20800588, 22429680, 23785128, 25351510, 27532257, 29121657, 30847666, 32481709, 32731933, 32894683, 33495597). In two families, this variant has been reported to segregate with disease in affected individuals (PMID: 15858117, 23140321). This variant has been identified in 6/282874 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		2	not provided	not provided	not provided

Last Updated: May 3, 2025

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