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

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Mar 8, 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:: RCV000769465.3

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]

Condition(s)

Name:: Cardiomyopathy (CMYO)
Synonyms:: Cardiomyopathies
Identifiers:: MONDO: MONDO:0004994; MedGen: C0878544; Human Phenotype Ontology: HP:0001638

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000900860	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario - Canadian Open Genetics Repository	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 12, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004356968	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 8, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 27532257, 29300372, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000900860

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario - Canadian Open Genetics Repository

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Apr 12, 2016)

germline

clinical testing

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

SCV004356968

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 8, 2023)

germline

clinical testing

PubMed (3)
[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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples.

Walsh R, Thomson KL, Ware JS, Funke BH, Woodley J, McGuire KJ, Mazzarotto F, Blair E, Seller A, Taylor JC, Minikel EV, Exome Aggregation Consortium, MacArthur DG, Farrall M, Cook SA, Watkins H.

Genet Med. 2017 Feb;19(2):192-203. doi: 10.1038/gim.2016.90. Epub 2016 Aug 17.

PubMed [citation]

PMID:: 27532257
PMCID:: PMC5116235

Adaptation and validation of the ACMG/AMP variant classification framework for MYH7-associated inherited cardiomyopathies: recommendations by ClinGen's Inherited Cardiomyopathy Expert Panel.

Kelly MA, Caleshu C, Morales A, Buchan J, Wolf Z, Harrison SM, Cook S, Dillon MW, Garcia J, Haverfield E, Jongbloed JDH, Macaya D, Manrai A, Orland K, Richard G, Spoonamore K, Thomas M, Thomson K, Vincent LM, Walsh R, Watkins H, Whiffin N, et al.

Genet Med. 2018 Mar;20(3):351-359. doi: 10.1038/gim.2017.218. Epub 2018 Jan 4.

PubMed [citation]

PMID:: 29300372
PMCID:: PMC5876064

See all PubMed Citations (3)

Details of each submission

From CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario - Canadian Open Genetics Repository, SCV000900860.1

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Color Diagnostics, LLC DBA Color Health, SCV004356968.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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