NM_000257.4(MYH7):c.1358G>T (p.Arg453Leu) AND Hypertrophic cardiomyopathy

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Apr 24, 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:: RCV000818531.11

Allele description [Variation Report for NM_000257.4(MYH7):c.1358G>T (p.Arg453Leu)]

NM_000257.4(MYH7):c.1358G>T (p.Arg453Leu)

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.1358G>T (p.Arg453Leu)

HGVS:

NC_000014.9:g.23429004C>A
NG_007884.1:g.11658G>T
NM_000257.4:c.1358G>TMANE SELECT
NP_000248.2:p.Arg453Leu
LRG_384t1:c.1358G>T
LRG_384:g.11658G>T
NC_000014.8:g.23898213C>A
NM_000257.2:c.1358G>T
NM_000257.3:c.1358G>T

Protein change:

R453L

Links:

dbSNP: rs397516101

NCBI 1000 Genomes Browser:

rs397516101

Molecular consequence:

NM_000257.4:c.1358G>T - 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
SCV000959150	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Sep 19, 2022)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 11133230, 12975413, 17599605, 24093860, 24111713, 21520333, 28492532
SCV004831329	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Apr 24, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25351510, 27532257, 33495597, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000959150

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Sep 19, 2022)

germline

clinical testing

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

SCV004831329

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(Apr 24, 2023)

germline

clinical testing

PubMed (4)
[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	1	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Beta-myosin heavy chain gene mutations and hypertrophic cardiomyopathy in Austrian children.

Greber-Platzer S, Marx M, Fleischmann C, Suppan C, Dobner M, Wimmer M.

J Mol Cell Cardiol. 2001 Jan;33(1):141-8.

PubMed [citation]

PMID:: 11133230

Mutations of the beta myosin heavy chain gene in hypertrophic cardiomyopathy: critical functional sites determine prognosis.

Woo A, Rakowski H, Liew JC, Zhao MS, Liew CC, Parker TG, Zeller M, Wigle ED, Sole MJ.

Heart. 2003 Oct;89(10):1179-85.

PubMed [citation]

PMID:: 12975413
PMCID:: PMC1767874

See all PubMed Citations (11)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000959150.6

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

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg453 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11133230, 12975413, 17599605, 24093860, 24111713; 20031618 23283745). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 235026). This missense change has been observed in individual(s) with clinical features of MYH7-related conditions (PMID: 21520333). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 453 of the MYH7 protein (p.Arg453Leu).

#	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, SCV004831329.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (4)

Description

This missense variant replaces arginine with leucine at codon 453 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 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 at least one individual affected with hypertrophic cardiomyopathy (PMID: 25351510, 33495597). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants occurring at the same codon: p.Arg453Cys, p.Arg453His, and p.Arg453Ser, are well documented pathogenic mutations (Clinvar variation ID: 14089, 42838, 14129), indicating that arginine at this position is important for MYH7 protein function. 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		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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