rs735712

chr14-23429851-G-Achr14-23429851-G-Cchr14-23429851-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000257.4(MYH7):c.1062C>T(p.Gly354=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0731 in 1,613,886 control chromosomes in the GnomAD database, including 4,547 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. G354G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.063 (359 hom., cov: 32)
  • Exomes 𝑓: 0.074 (4188 hom.)
• Consequence: MYH7 NM_000257.4 synonymous
• Clinical Significance: Benign reviewed by expert panel U:1 B:19
• Conservation: PhyloP100: -8.29

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 14-23429851-G-A is Benign according to our data. Variant chr14-23429851-G-A is described in ClinVar as [Benign]. Clinvar id is 42819.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr14-23429851-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-8.29 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0905 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4	c.1062C>T	p.Gly354=	synonymous_variant	12/40	ENST00000355349.4
MYH7	NM_001407004.1	c.1062C>T	p.Gly354=	synonymous_variant	11/39

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0632 AC: 9608 AN: 152020 Hom.: 360 Cov.: 32

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

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.: 35 AF XY: 0.0754 AC XY: 54865 AN XY: 727186

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.: 32 AF XY: 0.0622 AC XY: 4625 AN XY: 74372

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:1 Benign:19

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:9

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	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Sep 09, 2019	- -
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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Cardiomyopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 15, 2018	- -
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). -

Hypertrophic cardiomyopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	Cohesion Phenomics	Oct 10, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Uncertain:1

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. -

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

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

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

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	-0.91
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

Other links and lift over

dbSNP: rs735712; hg19: chr14-23899060;