Variant rs735712 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the c.1062C>T (p.Gly354=) variant in the MYH7 gene is 9.56% (1644/16510) of South Asian chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). LINK:https://erepo.genome.network/evrepo/ui/classification/CA010125/MONDO:0004994/002

Frequency

Genomes: 𝑓 0.063 ( 359 hom., cov: 32)

Exomes 𝑓: 0.074 ( 4188 hom. )

Consequence

MYH7
ENST00000355349.4 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:20

Conservation

PhyloP100: -8.29

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 Benign. Variant got -8 ACMG points.

BA1

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.1062C>T	p.Gly354=	synonymous_variant	12/40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1 linkuse as main transcript	c.1062C>T	p.Gly354=	synonymous_variant	11/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4 linkuse as main transcript	c.1062C>T	p.Gly354=	synonymous_variant	12/40	1	NM_000257.4	ENSP00000347507	P1

Frequencies

GnomAD3 genomes

AF:

0.0632

AC:

9608

AN:

152020

Hom.:

360

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0287

Gnomad AMI

AF:

0.251

Gnomad AMR

AF:

0.0741

Gnomad ASJ

AF:

0.0925

Gnomad EAS

AF:

0.0683

Gnomad SAS

AF:

0.0978

Gnomad FIN

AF:

0.0525

Gnomad MID

AF:

0.0886

Gnomad NFE

AF:

0.0762

Gnomad OTH

AF:

0.0699

GnomAD3 exomes

AF:

0.0703

AC:

17686

AN:

251444

Hom.:

734

AF XY:

0.0740

AC XY:

10062

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.0251

Gnomad AMR exome

AF:

0.0450

Gnomad ASJ exome

AF:

0.0982

Gnomad EAS exome

AF:

0.0677

Gnomad SAS exome

AF:

0.0998

Gnomad FIN exome

AF:

0.0555

Gnomad NFE exome

AF:

0.0769

Gnomad OTH exome

AF:

0.0794

GnomAD4 exome

AF:

0.0742

AC:

108412

AN:

1461748

Hom.:

4188

Cov.:

AF XY:

0.0754

AC XY:

54865

AN XY:

727186

show subpopulations

Gnomad4 AFR exome

AF:

0.0245

Gnomad4 AMR exome

AF:

0.0480

Gnomad4 ASJ exome

AF:

0.0976

Gnomad4 EAS exome

AF:

0.0539

Gnomad4 SAS exome

AF:

0.0986

Gnomad4 FIN exome

AF:

0.0588

Gnomad4 NFE exome

AF:

0.0757

Gnomad4 OTH exome

AF:

0.0730

GnomAD4 genome

AF:

0.0631

AC:

9601

AN:

152138

Hom.:

359

Cov.:

AF XY:

0.0622

AC XY:

4625

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.0286

Gnomad4 AMR

AF:

0.0740

Gnomad4 ASJ

AF:

0.0925

Gnomad4 EAS

AF:

0.0687

Gnomad4 SAS

AF:

0.0978

Gnomad4 FIN

AF:

0.0525

Gnomad4 NFE

AF:

0.0762

Gnomad4 OTH

AF:

0.0687

Alfa

AF:

0.0689

Hom.:

186

Bravo

AF:

0.0608

Asia WGS

AF:

0.0760

AC:

264

AN:

3478

EpiCase

AF:

0.0835

EpiControl

AF:

0.0830

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:20

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:9

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 18, 2008	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 25, 2012	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Sep 09, 2019	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided

Uncertain:1Benign:1

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	Allele frequency is common in at least one population database (frequency: 9.978% in gnomAD_Exomes) based on the frequency threshold of 0.637% for this gene. Variant was observed in a homozygous state in population databases more than expected for disease. A synonymous variant not located in a splice region. -

Cardiomyopathy

Benign:2

Benign, reviewed by expert panel	curation	ClinGen Cardiomyopathy Variant Curation Expert Panel	Dec 15, 2016	The filtering allele frequency of the c.1062C>T (p.Gly354=) variant in the MYH7 gene is 9.56% (1644/16510) of South Asian chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 15, 2018	- -

Hypertrophic cardiomyopathy

Benign:2

Benign, criteria provided, single submitter	clinical testing	Cohesion Phenomics	Oct 10, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Myosin storage myopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

MYH7-related skeletal myopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Dilated Cardiomyopathy, Dominant

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Left ventricular noncompaction cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 16, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Hypertrophic cardiomyopathy 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

6.3

DANN

Benign

0.71

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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