rs121913625

Variant names:

• chr14-23429005-G-A
• rs121913625
• NM_000257.4:c.1357C>T
• MYH7 p.Arg453Cys

Your query was ambiguous. Multiple possible variants found:

• chr14-23429005-G-A
• chr14-23429005-G-T
• chr14-23429005-G-C

Germline classificationCancer classification (beta)

Variant summary

Our verdict is

Pathogenic

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

. The variant received 20 ACMG points: 20P and 0B. PS3PM1PM2_SupportingPM5PP2PP3_ModeratePP5_Very_Strong

The NM_000257.4(MYH7):c.1357C>T (p.Arg453Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000372 (AC=6) in the gnomAD database across 1,614,098 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000147. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV006101161: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."" and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.R453L: Likely_pathogenic (ClinVar VariationId 235026, 2 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R453= (synonymous): Likely_benign (ClinVar VariationId 4809962, 1 star); p.R453= (synonymous): Likely_benign (ClinVar VariationId 1635083, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:29
• Conservation: PhyloP100: 1.75
• Publications: 102 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 1S

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

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

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

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, 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
• 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

Classification according to ACMG Germline Pathogenicity v2019

Specifications for MYH7 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PS3: Well-established functional study supports damaging effect (PS3); SCV006101161: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV000208734: Published functional studies demonstrate a damaging effect as reduced ATPase activity and enhanced calcium sensitivity result in a hyper-contractile state of the cardiac muscle (Palmer et al., 2004; Debold et al., 2007; Tajsharghi et al., 2008; Sommese et al., 2013; Bloemink et al., 2014); SCV000280298: The Seidman group has developed a mouse model with p.Arg453Cys that recapitulates an HCM phenotype (Palmer et al 2004, Debold et al 2007).; SCV000284255: Experimental studies have shown that this missense change affects MYH7 function (PMID: 15001446, 17351073, 23798412, 24344137).; SCV000564414: In vitro functional studies provide some evidence that this variant impacts protein function (PS2; PMID:23798412; PMID:24344137).; SCV000739964: "In addition, studies of mouse models harboring this alteration recapitulated HCM phenotype (Palmer BM et al. Am J Physiol Heart Circ Physiol. 2004;287(1):H91-9. Debold EP et al. Am J Physiol Heart Circ Physiol. 2007;293(1):H284-91)."; SCV001572573: Similar findings were present in a constructed human MYH7 protein (PMID: 23798412 )(PS3).; SCV004719132: Functional studies support the pathogenicity of this variant (Debold et al. 2007. PubMed ID: 17351073; Sommese et al. 2013. PubMed ID: 23798412).
• PM1: Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 6 pathogenic, 0 benign (OR vs. background: 65.0).
• PM2: Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.0000147 — borderline rare for AD+AR gene (threshold 0.0001) — PM2 supporting.
• PM5: Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.R453L: Likely_pathogenic (ClinVar VariationId 235026, 2 stars); Other variants at the same amino acid residue (not pathogenic): p.R453= (synonymous): Likely_benign (ClinVar VariationId 4809962, 1 star); p.R453= (synonymous): Likely_benign (ClinVar VariationId 1635083, 1 star)
• PP2: Missense in gene constrained for missense variation where missense is common disease mechanism (PP2); Missense in a gene constrained for missense variation (gnomAD Z-score: 6.806). ClinVar shows strong pathogenic missense enrichment: 625 P/LP and 50 B/LB missense entries (ratio 12.5×).
• PP3: Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).
• PP5: ClinVar ≥3 stars pathogenic — very strong (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 3 star(s).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000257.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH7	NM_000257.4	MANE Select	c.1357C>T	p.Arg453Cys	missense	Exon 14 of 40	NP_000248.2	P12883
	MYH7	NM_001407004.1		c.1357C>T	p.Arg453Cys	missense	Exon 13 of 39	NP_001393933.1	P12883

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH7	ENST00000355349.4	TSL:1 MANE Select	c.1357C>T	p.Arg453Cys	missense	Exon 14 of 40	ENSP00000347507.3	P12883
	MYH7	ENST00000858540.1		c.1357C>T	p.Arg453Cys	missense	Exon 14 of 40	ENSP00000528599.1
	MYH7	ENST00000965955.1		c.1357C>T	p.Arg453Cys	missense	Exon 14 of 40	ENSP00000636014.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461892 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74364

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
8	-	-	Hypertrophic cardiomyopathy 1 (8)
8	-	-	not provided (8)
5	-	-	Hypertrophic cardiomyopathy (5)
3	-	-	Primary familial hypertrophic cardiomyopathy (3)
2	-	-	Cardiomyopathy (2)
1	-	-	Cardiovascular phenotype (1)
1	-	-	MYH7-related disorder (1)
1	-	-	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		1.8
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-7.2	D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0060	D
Varity_R		0.75
gMVP		0.98
Mutation Taster		=14/86	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs121913625;

hg19: chr14-23898214;

COSMIC: COSV62516285;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar