NM_000257.4(MYH7):c.788T>C (p.Ile263Thr) AND Hypertrophic cardiomyopathy

Germline classification:: Pathogenic (5 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:: RCV000758021.15

Allele description [Variation Report for NM_000257.4(MYH7):c.788T>C (p.Ile263Thr)]

NM_000257.4(MYH7):c.788T>C (p.Ile263Thr)

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.788T>C (p.Ile263Thr)

Other names:

p.I263T:ATA>ACA; NM_000257.3(MYH7):c.788T>C

HGVS:

NC_000014.9:g.23431426A>G
NG_007884.1:g.9236T>C
NM_000257.4:c.788T>CMANE SELECT
NP_000248.2:p.Ile263Thr
LRG_384t1:c.788T>C
LRG_384:g.9236T>C
NC_000014.8:g.23900635A>G
NM_000257.2:c.788T>C
NM_000257.3:c.788T>C
P12883:p.Ile263Thr
c.788T>C

Protein change:

I263T

Links:

UniProtKB: P12883#VAR_004571; dbSNP: rs397516269

NCBI 1000 Genomes Browser:

rs397516269

Molecular consequence:

NM_000257.4:c.788T>C - 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
SCV000059656	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Apr 9, 2013)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 9829907, 12707239, 9140839, 15008060, 16335287, 22429680, 23074333, 20624503, 21425739, 24033266
SCV000564409	ClinGen Cardiomyopathy Variant Curation Expert Panel	reviewed by expert panel (ClinGen CMP ACMG Specifications v1)	Pathogenic (Dec 15, 2016)	germline	curation	PubMed (3) [See all records that cite these PMIDs] 9829907, 15008060, 29300372 Citation Link,
SCV000886776	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]
SCV000935029	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 17, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 9829907, 12707239, 15008060, 21425739, 24093860, 27247418, 27532257, 28492532
SCV004833585	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 28, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 27532257, 29300372, 25741868

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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	not provided	4	3	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	108544	not provided	clinical testing, curation

Citations

PubMed

The influence of the angiotensin I converting enzyme genotype in familial hypertrophic cardiomyopathy varies with the disease gene mutation.

Tesson F, Dufour C, Moolman JC, Carrier L, al-Mahdawi S, Chojnowska L, Dubourg O, Soubrier E, Brink P, Komajda M, Guicheney P, Schwartz K, Feingold J.

J Mol Cell Cardiol. 1997 Feb;29(2):831-8.

PubMed [citation]

PMID:: 9140839

Malignant mutations in hypertrophic cardiomyopathy: fact or fancy?

Brito D, Madeira H.

Rev Port Cardiol. 2005 Sep;24(9):1137-46. Review. English, Portuguese.

PubMed [citation]

PMID:: 16335287

See all PubMed Citations (16)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000059656.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	clinical testing	PubMed (10)

Description

The Ile263Thr variant in MYH7 has been reported in 7 individuals with HCM and se gregated with disease in >10 affected relatives (Tesson 1997, Tesson 1998, Brito 2003, Richard 2003, Brito 2005, Santos 2012). This variant was not identified i n large population studies. Isoleucine (Ile) at position is highly conserved in mammals and across evolutionarily distant species and the change to threonine (T hr) was predicted to be pathogenic using a computational tool clinically validat ed by our laboratory. This tool's pathogenic prediction is estimated to be corre ct 94% of the time (Jordan 2011). In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM) based upon segregat ion studies and absence from controls.

#	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		4	not provided	3	not provided

From ClinGen Cardiomyopathy Variant Curation Expert Panel, SCV000564409.5

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

Description

The c.788T>C (p.Ile263Thr) variant in MYH7 has been reported in >20 individuals with hypertrophic cardiomyopathy (PS4: PMID:15008060; PMID:9829907; PMID:12707239; PMID:22429680; PMID:20624503; Partners LMM ClinVar SCV000059656.5; SHaRe consortium, PMID: 30297972). This variant segregated with disease in 10 affected individuals (PP1_Strong: PMID:15008060; PMID:9829907). 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). 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, PP1_Strong, PM1, PM2, 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

From Center for Human Genetics, University of Leuven, SCV000886776.1

#	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

From Invitae, SCV000935029.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). For these reasons, this variant has been classified as Pathogenic. 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: 43106). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 9829907, 12707239, 15008060, 21425739, 24093860, 27247418, 27532257). This variant is present in population databases (rs397516269, gnomAD 0.0009%). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 263 of the MYH7 protein (p.Ile263Thr).

#	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, SCV004833585.1

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

Description

This missense variant replaces isoleucine with threonine at codon 263 of the MYH7 protein. 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). 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in greater than 20 individuals affected with hypertrophic cardiomyopathy (9140839, 9829907, 12707239, 15008060, 16335287, 20624503, 21425739, 22429680, 24093860, 24111713, 25611685, 27532257, 29300372, 30297972, 33495596). It has been shown that this variant segregates with disease in multiple affected individuals across multiple families (PMID: 29300372). This variant has been identified in 1/251460 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as 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: May 7, 2024

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