NM_000257.4(MYH7):c.676G>A (p.Ala226Thr) AND Hypertrophic cardiomyopathy

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 21, 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:: RCV000457952.12

Allele description [Variation Report for NM_000257.4(MYH7):c.676G>A (p.Ala226Thr)]

NM_000257.4(MYH7):c.676G>A (p.Ala226Thr)

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.676G>A (p.Ala226Thr)

HGVS:

NC_000014.9:g.23431641C>T
NG_007884.1:g.9021G>A
NM_000257.4:c.676G>AMANE SELECT
NP_000248.2:p.Ala226Thr
LRG_384t1:c.676G>A
LRG_384:g.9021G>A
NC_000014.8:g.23900850C>T
NM_000257.2:c.676G>A
NM_000257.3:c.676G>A

Protein change:

A226T

Links:

dbSNP: rs1057517773

NCBI 1000 Genomes Browser:

rs1057517773

Molecular consequence:

NM_000257.4:c.676G>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
SCV000546192	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 21, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 27247418, 27532257, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000546192

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 21, 2023)

germline

clinical testing

PubMed (3)
[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

Multidimensional structure-function relationships in human β-cardiac myosin from population-scale genetic variation.

Homburger JR, Green EM, Caleshu C, Sunitha MS, Taylor RE, Ruppel KM, Metpally RP, Colan SD, Michels M, Day SM, Olivotto I, Bustamante CD, Dewey FE, Ho CY, Spudich JA, Ashley EA.

Proc Natl Acad Sci U S A. 2016 Jun 14;113(24):6701-6. doi: 10.1073/pnas.1606950113. Epub 2016 May 31.

PubMed [citation]

PMID:: 27247418
PMCID:: PMC4914177

Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples.

Walsh R, Thomson KL, Ware JS, Funke BH, Woodley J, McGuire KJ, Mazzarotto F, Blair E, Seller A, Taylor JC, Minikel EV, Exome Aggregation Consortium, MacArthur DG, Farrall M, Cook SA, Watkins H.

Genet Med. 2017 Feb;19(2):192-203. doi: 10.1038/gim.2016.90. Epub 2016 Aug 17.

PubMed [citation]

PMID:: 27532257
PMCID:: PMC5116235

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000546192.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 226 of the MYH7 protein (p.Ala226Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of hypertrophic cardiomyopathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 372429). 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 disrupts the p.Ala226 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27247418, 27532257; Invitae). 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

Last Updated: Sep 29, 2024

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