NM_000257.4(MYH7):c.746G>A (p.Arg249Gln) AND Hypertrophic cardiomyopathy

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jan 7, 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:: RCV000229956.14

Allele description [Variation Report for NM_000257.4(MYH7):c.746G>A (p.Arg249Gln)]

NM_000257.4(MYH7):c.746G>A (p.Arg249Gln)

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.746G>A (p.Arg249Gln)

Other names:

p.R249Q:CGA>CAA

HGVS:

NC_000014.9:g.23431468C>T
NG_007884.1:g.9194G>A
NM_000257.4:c.746G>AMANE SELECT
NP_000248.2:p.Arg249Gln
LRG_384t1:c.746G>A
LRG_384:g.9194G>A
NC_000014.8:g.23900677C>T
NM_000257.2:c.746G>A
NM_000257.3:c.746G>A
P12883:p.Arg249Gln
c.746G>A

Protein change:

R249Q; ARG249GLN

Links:

UniProtKB: P12883#VAR_004569; OMIM: 160760.0002; dbSNP: rs3218713

NCBI 1000 Genomes Browser:

rs3218713

Molecular consequence:

NM_000257.4:c.746G>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
SCV000059652	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Jul 17, 2014)	germline	clinical testing	PubMed (16) [See all records that cite these PMIDs] 1552912, 7731997, 7662452, 11133230, 9140839, 10065021, 12707239, 12975413, 9826622, 24298987, 23233322, 1944483, 26914223, 27247418, 27532257, 24033266
SCV000284295	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 7, 2024)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 1944483, 7662452, 10065021, 23549607, 24691700, 25351510, 27532257, 27841901, 9826622, 28492532
SCV000886775	Center for Human Genetics, University of Leuven	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 31, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000059652

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Pathogenic
(Jul 17, 2014)

germline

clinical testing

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

SCV000284295

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 7, 2024)

germline

clinical testing

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

SCV000886775

Center for Human Genetics, University of Leuven

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Oct 31, 2018)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	1	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	10	5	not provided	not provided	not provided	clinical testing

Citations

PubMed

Characteristics and prognostic implications of myosin missense mutations in familial hypertrophic cardiomyopathy.

Watkins H, Rosenzweig A, Hwang DS, Levi T, McKenna W, Seidman CE, Seidman JG.

N Engl J Med. 1992 Apr 23;326(17):1108-14.

PubMed [citation]

PMID:: 1552912

Structural interpretation of the mutations in the beta-cardiac myosin that have been implicated in familial hypertrophic cardiomyopathy.

Rayment I, Holden HM, Sellers JR, Fananapazir L, Epstein ND.

Proc Natl Acad Sci U S A. 1995 Apr 25;92(9):3864-8.

PubMed [citation]

PMID:: 7731997
PMCID:: PMC42062

See all PubMed Citations (22)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000059652.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	10	not provided	not provided	clinical testing	PubMed (16)

Description

The p.Arg249Gln variant in MYH7 has been reported in >10 individuals with hypert rophic cardiomyopathy (HCM), including 2 de novo occurrences, and segregated wit h disease in >30 affected relatives from 3 families (Rosenzweig 1991, Watkins 19 92, Posen 1995, Arbustini 1998, Greber-Platzer 2001, Richard 2003, Woo 2003, Kas sem 2013). Additionally, this variant has been reported by other clinical labor atories in ClinVar (Variation ID: 14088) and was absent from large population st udies. Arginine (Arg) at position 249 is highly conserved in mammals and the ch ange to glutamine (Gln) was predicted to be pathogenic using a computational too l clinically validated by our laboratory. This tool's pathogenic prediction is e stimated to be correct 94% of the time (Jordan 2011). Moreover, this variant is located in the head domain of the MYH7 protein, where studies have shown that va riants in this region have an increased probability for causing disease (Walsh 2 017). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM based upon segregation studies, de novo occurrences, and absence from controls. ACMG/AMP criteria applied: PS4, PM6_Strong, PP1_Strong, PM2, PM1, PP3.

#	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		10	not provided	5	not provided

From Invitae, SCV000284295.9

#	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 arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 249 of the MYH7 protein (p.Arg249Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy and/or left ventricular non-compaction (PMID: 1944483, 7662452, 10065021, 23549607, 24691700, 25351510, 27532257, 27841901). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14088). 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: 9826622). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 Center for Human Genetics, University of Leuven, SCV000886775.1

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

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

Last Updated: Apr 15, 2024

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