NM_000257.4(MYH7):c.1358G>A (p.Arg453His) 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:: RCV000195545.17

Allele description [Variation Report for NM_000257.4(MYH7):c.1358G>A (p.Arg453His)]

NM_000257.4(MYH7):c.1358G>A (p.Arg453His)

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>A (p.Arg453His)

Other names:

p.R453H:CGC>CAC; NM_000257.3(MYH7):c.1358G>A

HGVS:

NC_000014.9:g.23429004C>T
NG_007884.1:g.11658G>A
NM_000257.4:c.1358G>AMANE SELECT
NP_000248.2:p.Arg453His
LRG_384t1:c.1358G>A
LRG_384:g.11658G>A
NC_000014.8:g.23898213C>T
NM_000257.2:c.1358G>A
NM_000257.3:c.1358G>A
P12883:p.Arg453His
c.1358G>A

Protein change:

R453H

Links:

UniProtKB: P12883#VAR_042788; dbSNP: rs397516101

NCBI 1000 Genomes Browser:

rs397516101

Molecular consequence:

NM_000257.4:c.1358G>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
SCV000059369	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely pathogenic (Jan 12, 2013)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 20428263, 20800588, 15858117, 22429680, 23074333, 21835320, 24033266
SCV000253816	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 13, 2022)	germline	clinical testing	PubMed (16) [See all records that cite these PMIDs] 20428263, 8655135, 11133230, 12975413, 17351073, 23283745, 23798412, 24344137, 15858117, 20800588, 21835320, 22429680, 23140321, 24093860, 27247418, 28492532
SCV000564415	ClinGen Cardiomyopathy Variant Curation Expert Panel	reviewed by expert panel (ClinGen CMP ACMG Specifications v1)	Pathogenic (Dec 15, 2016)	germline	curation	PubMed (7) [See all records that cite these PMIDs] 22429680, 15858117, 20428263, 20800588, 27532257, 21835320, 29300372 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000059369

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Likely pathogenic
(Jan 12, 2013)

germline

clinical testing

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

SCV000253816

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 13, 2022)

germline

clinical testing

PubMed (16)
[See all records that cite these PMIDs]

SCV000564415

ClinGen Cardiomyopathy Variant Curation Expert Panel

reviewed by expert panel

(ClinGen CMP ACMG Specifications v1)

Pathogenic
(Dec 15, 2016)

germline

curation

PubMed (7)
[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	not provided	2	2	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Cardiac structural and sarcomere genes associated with cardiomyopathy exhibit marked intolerance of genetic variation.

Pan S, Caleshu CA, Dunn KE, Foti MJ, Moran MK, Soyinka O, Ashley EA.

Circ Cardiovasc Genet. 2012 Dec;5(6):602-10. doi: 10.1161/CIRCGENETICS.112.963421. Epub 2012 Oct 16.

PubMed [citation]

PMID:: 23074333
PMCID:: PMC3526690

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

See all PubMed Citations (20)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000059369.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (7)

Description

The Arg453His variant has been reported in 5 individuals with HCM (Haluza 2001, Yu 2005, Millat 2010, Olivotto 2011, Santos 2012) and in one African American in dividual with HCM previously tested by our laboratory (LMM unpublished data). I n one individual, the variant had occurred ?de novo? but the presence of a secon d, pathogenic MYH7 variant (Arg403Trp) left the clinical significance of the Arg 453His variant uncertain (Haluza 2001). This variant has not been identified in large European American and African American populations by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS/), which is consistent with a p athogenic role. However, we cannot exclude that it may be common in other popula tions. Arginine (Arg) at position 453 is conserved in evolution and 3 other vari ants at that position have been reported (Arg453Cys, Arg453Ser, Arg453Leu), sugg esting that a change would not be tolerated. The Arg453His variant was also pred icted to be pathogenic using a computational tool, which was validated by our la boratory using a set of cardiomyopathy variants with well-established clinical s ignificance. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, this variant is likely to be pathogenic, th ough additional studies are required to fully establish its clinical significanc e.

#	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		2	not provided	2	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000253816.11

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (16)

Description

This missense change has been observed to co-occur in individuals with a different variant in MYH7 that has been determined to be pathogenic (PMID: 20428263), but the significance of this finding is unclear. For these reasons, this variant has been classified as 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: 8655135, 11133230, 12975413, 17351073, 23283745, 23798412, 24344137, 27247418). 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: 42838). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 15858117, 20800588, 21835320, 22429680, 23140321, 24093860, 27247418). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 453 of the MYH7 protein (p.Arg453His).

#	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, SCV000564415.5

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

Description

The c.1358G>A (p.Arg453His) variant in MYH7 has been reported in >12 individuals with hypertrophic cardiomyopathy (PS4; PMID:27532257; PMID:20428263; PMID:15858117; PMID:20800588; PMID:21835320; PMID:22429680; Partners LMM ClinVar SCV000059369.5; Invitae ClinVar SCV000253816.4; SHaRe consortium, PMID: 30297972). This variant was been identified as a de novo occurrence in 1 proband with hypertrophic cardiomyopathy (PM6; PMID:20428263). 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). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). A different pathogenic missense variant has been previously identified at this codon which may indicate that this residue is critical to the function of the protein (PM5; c.1357C>T p.Arg453Cys; ClinVar Variation ID 14089). 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; PM1; PM2; PM5; PM6; 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

Last Updated: Sep 29, 2024

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