rs2069542

Positions:

• chr14-23431585-G-A
• chr14-23431585-G-C

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.732C>T (p.Phe244=) variant in the MYH7 gene is 53.63% (5704/10406) of African 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/CA016723/MONDO:0004994/002

• Frequency:
  • Genomes: 𝑓 0.27 (7679 hom., cov: 32)
  • Exomes 𝑓: 0.16 (23467 hom.)
• Consequence: MYH7 NM_000257.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.0008311
• Clinical Significance: Benign reviewed by expert panel U:1 B:22
• Conservation: PhyloP100: 0.0810

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]

ACMG classification

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	c.732C>T	p.Phe244=	splice_region_variant, synonymous_variant	8/40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.732C>T	p.Phe244=	splice_region_variant, synonymous_variant	7/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.732C>T	p.Phe244=	splice_region_variant, synonymous_variant	8/40	1	NM_000257.4	ENSP00000347507	P1

Frequencies

GnomAD3 genomes AF: 0.265 AC: 40281 AN: 152108 Hom.: 7658 Cov.: 32

Gnomad AFR AF: 0.545

Gnomad AMI AF: 0.310

Gnomad AMR AF: 0.181

Gnomad ASJ AF: 0.208

Gnomad EAS AF: 0.0735

Gnomad SAS AF: 0.187

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.160

Gnomad OTH AF: 0.246

GnomAD3 exomes AF: 0.175 AC: 44019 AN: 251490 Hom.: 5367 AF XY: 0.173 AC XY: 23493 AN XY: 135922

Gnomad AFR exome AF: 0.549

Gnomad AMR exome AF: 0.114

Gnomad ASJ exome AF: 0.217

Gnomad EAS exome AF: 0.0701

Gnomad SAS exome AF: 0.190

Gnomad FIN exome AF: 0.110

Gnomad NFE exome AF: 0.161

Gnomad OTH exome AF: 0.184

GnomAD4 exome AF: 0.165 AC: 240991 AN: 1461880 Hom.: 23467 Cov.: 35 AF XY: 0.165 AC XY: 120195 AN XY: 727240

Gnomad4 AFR exome AF: 0.557

Gnomad4 AMR exome AF: 0.122

Gnomad4 ASJ exome AF: 0.218

Gnomad4 EAS exome AF: 0.0498

Gnomad4 SAS exome AF: 0.188

Gnomad4 FIN exome AF: 0.115

Gnomad4 NFE exome AF: 0.157

Gnomad4 OTH exome AF: 0.188

GnomAD4 genome AF: 0.265 AC: 40342 AN: 152226 Hom.: 7679 Cov.: 32 AF XY: 0.257 AC XY: 19109 AN XY: 74452

Gnomad4 AFR AF: 0.545

Gnomad4 AMR AF: 0.181

Gnomad4 ASJ AF: 0.208

Gnomad4 EAS AF: 0.0737

Gnomad4 SAS AF: 0.187

Gnomad4 FIN AF: 0.109

Gnomad4 NFE AF: 0.160

Gnomad4 OTH AF: 0.252

Alfa AF: 0.193 Hom.: 3487

Bravo AF: 0.279

Asia WGS AF: 0.171 AC: 591 AN: 3478

EpiCase AF: 0.180

EpiControl AF: 0.178

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:22

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:9

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 18, 2008	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
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	PreventionGenetics, part of Exact Sciences	-	- -

not provided Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	13 reputable source/s reports the variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation. Allele frequency is common in at least one population database (frequency: 54.866% 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. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Cardiomyopathy Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 09, 2018	- -
Benign, reviewed by expert panel	curation	ClinGen Cardiomyopathy Variant Curation Expert Panel	Dec 15, 2016	The filtering allele frequency of the c.732C>T (p.Phe244=) variant in the MYH7 gene is 53.63% (5704/10406) of African 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	Cohesion Phenomics	Oct 10, 2022	- -

Dilated cardiomyopathy 1S 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

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. -

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. -

Left ventricular noncompaction cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hypertrophic cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

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

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	2.4
DANN	Benign	0.86

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00083
dbscSNV1_RF	Benign	0.10
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

Other links and lift over

dbSNP: rs2069542; hg19: chr14-23900794; COSMIC: COSV62521944;