rs2069541

Positions:

• chr14-23431803-T-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.597A>G (p.Ala199=) variant in the MYH7 gene is 1.44% (1013/66740) of European 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/CA016520/MONDO:0004994/002

• Frequency:
  • Genomes: 𝑓 0.0087 (9 hom., cov: 33)
  • Exomes 𝑓: 0.014 (178 hom.)
• Consequence: MYH7 NM_000257.4 synonymous
• Clinical Significance: Benign reviewed by expert panel B:25
• Conservation: PhyloP100: -3.96

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.597A>G	p.Ala199=	synonymous_variant	7/40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.597A>G	p.Ala199=	synonymous_variant	6/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.597A>G	p.Ala199=	synonymous_variant	7/40	1	NM_000257.4	ENSP00000347507	P1

Frequencies

GnomAD3 genomes AF: 0.00874 AC: 1331 AN: 152244 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00244

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00759

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00954

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0147

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.0103 AC: 2580 AN: 251494 Hom.: 26 AF XY: 0.0112 AC XY: 1518 AN XY: 135920

Gnomad AFR exome AF: 0.00271

Gnomad AMR exome AF: 0.00653

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0118

Gnomad FIN exome AF: 0.00259

Gnomad NFE exome AF: 0.0158

Gnomad OTH exome AF: 0.0138

GnomAD4 exome AF: 0.0138 AC: 20221 AN: 1461874 Hom.: 178 Cov.: 34 AF XY: 0.0138 AC XY: 10056 AN XY: 727238

Gnomad4 AFR exome AF: 0.00209

Gnomad4 AMR exome AF: 0.00693

Gnomad4 ASJ exome AF: 0.00187

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0125

Gnomad4 FIN exome AF: 0.00315

Gnomad4 NFE exome AF: 0.0159

Gnomad4 OTH exome AF: 0.0112

GnomAD4 genome AF: 0.00874 AC: 1332 AN: 152362 Hom.: 9 Cov.: 33 AF XY: 0.00816 AC XY: 608 AN XY: 74508

Gnomad4 AFR AF: 0.00243

Gnomad4 AMR AF: 0.00758

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00996

Gnomad4 FIN AF: 0.00235

Gnomad4 NFE AF: 0.0147

Gnomad4 OTH AF: 0.00994

Alfa AF: 0.0135 Hom.: 31

Bravo AF: 0.00961

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.0165

EpiControl AF: 0.0177

ClinVar

Significance: Benign

Submissions summary: Benign:25

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:9

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 02, 2010	The Ala199Ala silent variant is not expected to have clinical significance becau se it does not alter an amino acid residue and is not located near a splice junc tion. In addition, it is present in 1-3% of the general population (dbSNP rs2069 541). -
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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	Feb 10, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Sep 24, 2019	- -

Cardiomyopathy Benign:4

Benign, reviewed by expert panel	curation	ClinGen Cardiomyopathy Variant Curation Expert Panel	Dec 15, 2016	The filtering allele frequency of the c.597A>G (p.Ala199=) variant in the MYH7 gene is 1.44% (1013/66740) of European 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	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Nov 07, 2022	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 13, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	- -

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. -

Dilated Cardiomyopathy, Dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Left ventricular noncompaction cardiomyopathy Benign:1

Likely 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 29, 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

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.22
DANN	Benign	0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2069541; hg19: chr14-23901012;