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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:
RCV000758021.16

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:
4

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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000059656Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(LMM Criteria)
Pathogenic
(Apr 9, 2013)
germlineclinical testing

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

SCV000564409ClinGen Cardiomyopathy Variant Curation Expert Panel
reviewed by expert panel

(ClinGen CMP ACMG Specifications v1)
Pathogenic
(Dec 15, 2016)
germlinecuration

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV000886776Center for Human Genetics, University of Leuven
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Oct 31, 2018)
germlineclinical testing

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

SCV000935029Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Sep 17, 2023)
germlineclinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV004833585All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Apr 28, 2023)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot provided1not providednot providednot providedclinical testing
not providedgermlineunknown1not providednot provided108544not providedclinical testing, curation
not providedgermlinenot provided43not providednot providednot providedclinical testing

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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided4not providednot providedclinical 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided4not provided3not provided

From ClinGen Cardiomyopathy Variant Curation Expert Panel, SCV000564409.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration 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

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot provided1not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000935029.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From All of Us Research Program, National Institutes of Health, SCV004833585.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown108544not providednot provided1not providednot providednot provided

Last Updated: Sep 29, 2024