chr14-23420220-C-T

Variant names:

• chr14-23420220-C-T
• rs45554236
• NM_000257.4:c.3351G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the c.3351G>A (p.Glu1117=) variant in the MYH7 gene is 0.34% (212/55890) 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/CA013640/MONDO:0004994/002

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0036 (27 hom.)
• Consequence: MYH7 ENST00000355349.4 synonymous
• Clinical Significance: Benign reviewed by expert panel U:1 B:23
• Conservation: PhyloP100: 0.468
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1S

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• MYH7-related skeletal myopathy

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• myopathy, myosin storage, autosomal recessive

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• myopathy, myosin storage, autosomal dominant

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• congenital myopathy 7A, myosin storage, autosomal dominant

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Ebstein anomaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hyaline body myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• left ventricular noncompaction

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000355349.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH7	NM_000257.4	MANE Select	c.3351G>A	p.Glu1117Glu	synonymous	Exon 27 of 40	NP_000248.2
	MYH7	NM_001407004.1		c.3351G>A	p.Glu1117Glu	synonymous	Exon 26 of 39	NP_001393933.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH7	ENST00000355349.4	TSL:1 MANE Select	c.3351G>A	p.Glu1117Glu	synonymous	Exon 27 of 40	ENSP00000347507.3
	MYH7	ENST00000713768.1		c.3351G>A	p.Glu1117Glu	synonymous	Exon 27 of 41	ENSP00000519070.1
	MYH7	ENST00000713769.1		c.3351G>A	p.Glu1117Glu	synonymous	Exon 26 of 39	ENSP00000519071.1

Frequencies

GnomAD3 genomes AF: 0.00212 AC: 320 AN: 151248 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000677

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000661

Gnomad ASJ AF: 0.00203

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000421

Gnomad FIN AF: 0.00124

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00379

Gnomad OTH AF: 0.00194

GnomAD2 exomes AF: 0.00206 AC: 503 AN: 244252 AF XY: 0.00207

Gnomad AFR exome AF: 0.000391

Gnomad AMR exome AF: 0.000495

Gnomad ASJ exome AF: 0.000808

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00104

Gnomad NFE exome AF: 0.00375

Gnomad OTH exome AF: 0.00217

GnomAD4 exome AF: 0.00360 AC: 5241 AN: 1457814 Hom.: 27 Cov.: 34 AF XY: 0.00352 AC XY: 2553 AN XY: 725108

African (AFR) AF: 0.000389 AC: 13 AN: 33426

American (AMR) AF: 0.000426 AC: 19 AN: 44598

Ashkenazi Jewish (ASJ) AF: 0.00119 AC: 31 AN: 26068

East Asian (EAS) AF: 0.00 AC: 0 AN: 39568

South Asian (SAS) AF: 0.000967 AC: 83 AN: 85844

European-Finnish (FIN) AF: 0.00142 AC: 73 AN: 51270

Middle Eastern (MID) AF: 0.000527 AC: 3 AN: 5692

European-Non Finnish (NFE) AF: 0.00437 AC: 4852 AN: 1111054

Other (OTH) AF: 0.00277 AC: 167 AN: 60294

GnomAD4 genome AF: 0.00211 AC: 320 AN: 151366 Hom.: 0 Cov.: 31 AF XY: 0.00196 AC XY: 145 AN XY: 73938

African (AFR) AF: 0.000675 AC: 28 AN: 41470

American (AMR) AF: 0.000660 AC: 10 AN: 15158

Ashkenazi Jewish (ASJ) AF: 0.00203 AC: 7 AN: 3444

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.000422 AC: 2 AN: 4744

European-Finnish (FIN) AF: 0.00124 AC: 13 AN: 10526

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00379 AC: 256 AN: 67616

Other (OTH) AF: 0.00192 AC: 4 AN: 2086

Alfa AF: 0.00256 Hom.: 2

Bravo AF: 0.00187

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	5	not provided (5)
-	-	3	Cardiomyopathy (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Congenital myopathy with fiber type disproportion;C1834481:Dilated cardiomyopathy 1S;C1842160:Myosin storage myopathy;C1850709:Myopathy, myosin storage, autosomal recessive;C3495498:Hypertrophic cardiomyopathy 1;C4552004:MYH7-related skeletal myopathy (1)
-	-	1	Dilated Cardiomyopathy, Dominant (1)
-	-	1	Hypertrophic cardiomyopathy (1)
-	1	-	Hypertrophic cardiomyopathy 1 (1)
-	-	1	Left ventricular noncompaction cardiomyopathy (1)
-	-	1	MYH7-related skeletal myopathy (1)
-	-	1	Myosin storage myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	7.3
DANN	Benign	0.88
PhyloP100		0.47
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs45554236; hg19: chr14-23889429; COSMIC: COSV108170769; COSMIC: COSV108170769;