rs397516269

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS4PP3PM1PM2PP1_Strong

This summary comes from the ClinGen Evidence Repository: 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 LINK:https://erepo.genome.network/evrepo/ui/classification/CA016824/MONDO:0005045/002

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:12

Conservation

PhyloP100: 9.12

Variant links:

Genes affected

MYH7 (HGNC:7577): (myosin heavy chain 7) Muscle myosin is a hexameric protein containing 2 heavy chain subunits, 2 alkali light chain subunits, and 2 regulatory light chain subunits. This gene encodes the beta (or slow) heavy chain subunit of cardiac myosin. It is expressed predominantly in normal human ventricle. It is also expressed in skeletal muscle tissues rich in slow-twitch type I muscle fibers. Changes in the relative abundance of this protein and the alpha (or fast) heavy subunit of cardiac myosin correlate with the contractile velocity of cardiac muscle. Its expression is also altered during thyroid hormone depletion and hemodynamic overloading. Mutations in this gene are associated with familial hypertrophic cardiomyopathy, myosin storage myopathy, dilated cardiomyopathy, and Laing distal myopathy. [provided by RefSeq, May 2022]

MYH7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

PM1

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PP1

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH7	NM_000257.4 link	c.788T>C	p.Ile263Thr	missense_variant	Exon 9 of 40	ENST00000355349.4	NP_000248.2	P12883
MYH7	NM_001407004.1 link	c.788T>C	p.Ile263Thr	missense_variant	Exon 8 of 39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4 link	c.788T>C	p.Ile263Thr	missense_variant	Exon 9 of 40	1	NM_000257.4	ENSP00000347507.3		P12883

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251460

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461824

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy

Pathogenic:5

Dec 15, 2016

ClinGen Cardiomyopathy Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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 -

Apr 09, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). This variant is present in population databases (rs397516269, gnomAD 0.0009%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 9829907, 12707239, 15008060, 21425739, 24093860, 27247418, 27532257). ClinVar contains an entry for this variant (Variation ID: 43106). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. 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. -

Apr 28, 2023

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 31, 2018

Center for Human Genetics, University of Leuven

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy

Pathogenic:2

Apr 12, 2016

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 08, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided

Pathogenic:2

Jun 23, 2015

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. MYH7 p.Ile263Thr (c.788T>C) The variant has been seen in at least 5 unrelated cases. The database curated by the Seidman group notes that the variant was first reported in an individual with HCM by Tesson et al (1997) but was mistakenly referred to as p.Ile263Trp (http://genepath.med.harvard.edu/seidman//cg3/muts/MYH7_Ile263Thr.html). The same group did later report a family with two affected members with "I263T", presumably the same family and variant (Tesson et al 1998). Richard et al (2003) reported one HCM patient with this variant in their French cohort. Brito et al (2003, 2005) reported the variant in multiple family members of two unrelated Portugese families. Unfortunately only the abstracts are available so we could not confirm details. Millat et al (2010) observed the variant in one individual with HCM in their French cohort (appears to be distinct from the Richard et al cohort). In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. The isoleucine at codon 263 is conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at this codon (p.Ile263Met, which we consider of uncertain significance, probably disease causing) and a nearby codon (p.Gly256Glu). In total the variant has not been seen in ~5700 published controls and publicly available population datasets. There is no variation at codon 263 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~5500 Caucasian and African American individuals (as of 1/16/2012). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 1/16/2012). The variant was not observed in the following published control samples: 100 (Tesson et al 1998), 100 (Richard et al 2003). -

May 23, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 9829907, 12707239, 27737317, 23074333, 21425739, 16335287, 22429680, 24014347, 20624503, 22857948, 24093860, 9140839, 27532257, 27247418, 25937619, 29300372, 30297972, 31589614, 35653365, 28193612, 31513939, 33258288, 33586461, 36264615, 37652022, 15008060) -

Cardiovascular phenotype

Pathogenic:2

Jun 03, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.I263T pathogenic mutation (also known as c.788T>C), located in coding exon 7 of the MYH7 gene, results from a T to C substitution at nucleotide position 788. The isoleucine at codon 263 is replaced by threonine, an amino acid with similar properties. This mutation was identified in multiple individuals with hypertrophic cardiomyopathy and was shown to segregate with disease (Tesson F et al. Hum. Mutat., 1998;12:385-92; Richard P et al. Circulation, 2003 May;107:2227-32; Brito D et al. Rev Port Cardiol, 2005 Sep;24:1137-46; Santos S et al. BMC Med. Genet., 2012 Mar;13:17; Homburger JR et al. Proc. Natl. Acad. Sci. U.S.A., 2016 06;113:6701-6; Walsh R et al. Genet. Med., 2017 02;19:192-203; Kelly MA et al. Genet. Med., 2018 03;20:351-359). In some families, reduced penetrance was noted (Tesson F et al. Hum. Mutat., 1998;12:385-92; Brito D et al. Rev Port Cardiol, 2005 Sep;24:1137-46). This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). In addition, this variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Feb 16, 2022

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy 1

Pathogenic:1

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

CardioboostCm

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.88

M_CAP

Pathogenic

0.99

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

2.9

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-4.1

REVEL

Pathogenic

0.93

Sift

Uncertain

0.0070

Sift4G

Pathogenic

0.0

Polyphen

0.19

Vest4

0.98

MutPred

0.89

Loss of stability (P = 0.0129);

MVP

0.97

MPC

2.3

ClinPred

0.98

GERP RS

3.5

Varity_R

0.67

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over