rs730880833

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PS4_SupportingPM2PP3

This summary comes from the ClinGen Evidence Repository: The NM_000257.4(MYH7):c.341T>C (p.Ile114Thr) variant has been identified in 4 individuals with HCM (PS4_Supporting; Restrepo-Cordoba 2017 PMID:28138913; GeneDx pers. comm.; Invitae pers. comm.). This variant has also been identified in 1 individual with DCM who also carried a truncating variant in TTN and an individual with heart disease and sensory disfunction (Ambry pers. comm.; LMM pers. comm.). This variant was identified in 0.0009% (1/113612) of European chromosomes by gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting, PM2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA013685/MONDO:0005045/002

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MYH7
ENST00000355349.4 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:7

Conservation

PhyloP100: 9.07

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PS4

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

PM2

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/exons	MANE	Protein	UniProt
MYH7	NM_000257.4 linkuse as main transcript	c.341T>C	p.Ile114Thr	missense_variant	4/40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1 linkuse as main transcript	c.341T>C	p.Ile114Thr	missense_variant	3/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4 linkuse as main transcript	c.341T>C	p.Ile114Thr	missense_variant	4/40	1	NM_000257.4	ENSP00000347507	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251332

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135850

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy

Uncertain:2

Uncertain significance, reviewed by expert panel	curation	ClinGen Cardiomyopathy Variant Curation Expert Panel	Mar 31, 2021	The NM_000257.4(MYH7):c.341T>C (p.Ile114Thr) variant has been identified in 4 individuals with HCM (PS4_Supporting; Restrepo-Cordoba 2017 PMID:28138913; GeneDx pers. comm.; Invitae pers. comm.). This variant has also been identified in 1 individual with DCM who also carried a truncating variant in TTN and an individual with heart disease and sensory disfunction (Ambry pers. comm.; LMM pers. comm.). This variant was identified in 0.0009% (1/113612) of European chromosomes by gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting, PM2, PP3. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 14, 2023	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 114 of the MYH7 protein (p.Ile114Thr). This variant is present in population databases (rs730880833, gnomAD 0.0009%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 28138913). ClinVar contains an entry for this variant (Variation ID: 181300). 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%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 15, 2018

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Ile114Thr variant in MYH7 has been reported in 1 individual with HCM (Restrepo-Cordoba 20 17). It has also been identified in 1/111556 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs73088083 3). This variant was predicted to be pathogenic using a computational tool clini cally validated by our laboratory. This tool's pathogenic prediction is estimate d to be correct 94% of the time (Jordan 2011). In summary, while there is some s uspicion for a pathogenic role, the clinical significance of the p.Ile114Thr var iant is uncertain. ACMG/AMP Criteria applied: PM2; PP3. -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Aug 17, 2020

This missense variant replaces isoleucine with threonine at codon 114 of the MYH7 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 28138913). This variant has been identified in 1/251332 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Congenital myopathy with fiber type disproportion;C1834481:Dilated cardiomyopathy 1S;C1842160:Myosin storage myopathy;C1850709:Myopathy, myosin storage, autosomal recessive;C3495498:Hypertrophic cardiomyopathy 1;C4552004:MYH7-related skeletal myopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 20, 2021

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 31, 2020

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28138913, 21310275) -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 11, 2020

The p.I114T variant (also known as c.341T>C), located in coding exon 2 of the MYH7 gene, results from a T to C substitution at nucleotide position 341. The isoleucine at codon 114 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in a hypertrophic cardiomyopathy (HCM) cohort (Alejandra Restrepo-Cordoba M et al. J Cardiovasc Transl Res, 2017 Feb;10:35-46). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

CardioboostCm

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.95

Eigen

Pathogenic

0.77

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.98

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.1

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-4.0

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.012

Polyphen

0.82

Vest4

0.95

MutPred

0.76

Gain of catalytic residue at S118 (P = 4e-04);

MVP

0.98

MPC

2.4

ClinPred

0.99

GERP RS

3.8

Varity_R

0.90

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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