rs149103761

Positions:

• chr14-23419559-G-A
• chr14-23419559-G-T

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.3777C>T (p.His1259=) variant in the MYH7 gene is 0.14% (22/10406) 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/CA014078/MONDO:0004994/002

• Frequency:
  • Genomes: 𝑓 0.00046 (1 hom., cov: 31)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: MYH7 NM_000257.4 synonymous
• Clinical Significance: Benign reviewed by expert panel B:12
• Conservation: PhyloP100: -0.226

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.3777C>T	p.His1259=	synonymous_variant	28/40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.3777C>T	p.His1259=	synonymous_variant	27/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.3777C>T	p.His1259=	synonymous_variant	28/40	1	NM_000257.4	ENSP00000347507	P1

Frequencies

GnomAD3 genomes AF: 0.000467 AC: 71 AN: 152006 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00172

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000107 AC: 27 AN: 251454 Hom.: 1 AF XY: 0.0000957 AC XY: 13 AN XY: 135900

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.0000289

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: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000301 AC: 44 AN: 1461886 Hom.: 0 Cov.: 44 AF XY: 0.0000261 AC XY: 19 AN XY: 727244

Gnomad4 AFR exome AF: 0.000986

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000629

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.000460 AC: 70 AN: 152124 Hom.: 1 Cov.: 31 AF XY: 0.000511 AC XY: 38 AN XY: 74356

Gnomad4 AFR AF: 0.00169

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000173 Hom.: 0

Bravo AF: 0.000419

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: reviewed by expert panel

Submissions by phenotype

Cardiomyopathy Benign:4

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 10, 2019	- -
Benign, reviewed by expert panel	curation	ClinGen Cardiomyopathy Variant Curation Expert Panel	Dec 15, 2016	The filtering allele frequency of the c.3777C>T (p.His1259=) variant in the MYH7 gene is 0.14% (22/10406) 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	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	May 16, 2023	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 11, 2024	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 26, 2017	Variant summary: The MYH7 c.3777C>T (p.His1259His) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 23/121404 control chromosomes (1 homozygote), predominantly observed in the African subpopulation at a frequency of 0.002114 (22/10406). This frequency is about 2 times the estimated maximal expected allele frequency of a pathogenic MYH7 variant (0.0012508), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign and one lab classified it as VUS, all without evidence for independent evaluaiton. Taken together, this variant is classified as likely benign. -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 14, 2011	His1259His in exon 28 of MYH7: This variant has been reported in the SNP databas e (rs149103761; allele frequency = n/a). It does not change an amino acid and do es not affect the splice consensus sequence. This makes a disease causing role v ery unlikely. His1259His in exon 28 of MYH7 (rs149103761; allele frequency = n/ a) -

Hypertrophic cardiomyopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	Cohesion Phenomics	Sep 27, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 03, 2024	- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 09, 2018

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.4
DANN	Benign	0.86

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

Other links and lift over

dbSNP: rs149103761; hg19: chr14-23888768;