rs45611033

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PS4_ModeratePM2PP3

This summary comes from the ClinGen Evidence Repository: The NM_000257.4(MYH7):c.3133C>T (p.Arg1045Cys) variant has been identified in at least 12 individuals with HCM (PS4_Moderate; Olivotto 2008 PMID:18533079; Bos 2014 PMID:24793961; Homburger 2016 PMID:27247418; Rubattu 2016 PMID:27483260; Cecconi 2016 PMID:27600940; Walsh 2017 PMID:27532257; Michels 2017 PMID:28005231) and in an additional individual with early-onset DCM that also carried a de novo TNNC1 variant (Hershberger 2008 PMID:19412328; Hershberger 2010 PMID:20215591; Rampersaud 2011 PMID:21483645; Pinto 2011; PMID:21832052). This variant was identified in 0.00152% (FAF 95% CI; 5/129168) of European chromosomes by gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate, PM2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA013367/MONDO:0005045/002

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:11U:2

Conservation

PhyloP100: 3.93

Publications

18 publications found

Variant links:

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

MYH7 links:

ENSG00000294572 (HGNC:):

ENSG00000294572 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PS4

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

PM2

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

PP3

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH7	NM_000257.4 link	c.3133C>T	p.Arg1045Cys	missense_variant	Exon 25 of 40	ENST00000355349.4	NP_000248.2	P12883
MYH7	NM_001407004.1 link	c.3133C>T	p.Arg1045Cys	missense_variant	Exon 24 of 39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYH7	ENST00000355349.4 link	c.3133C>T	p.Arg1045Cys	missense_variant	Exon 25 of 40	1	NM_000257.4	ENSP00000347507.3	P12883
MYH7	ENST00000713768.1 link	c.3133C>T	p.Arg1045Cys	missense_variant	Exon 25 of 41			ENSP00000519070.1
MYH7	ENST00000713769.1 link	c.3133C>T	p.Arg1045Cys	missense_variant	Exon 24 of 39			ENSP00000519071.1
ENSG00000294572	ENST00000724465.1 link	n.175G>A		non_coding_transcript_exon_variant	Exon 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000239

AC:

AN:

251472

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000390

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

1112012

Other (OTH)

AF:

0.0000497

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152286

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41544

American (AMR)

AF:

0.00

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.555

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000421

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:11Uncertain:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1

Feb 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 27, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 30, 2023

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in a patient with unexplained sudden cardiac death (SCD) and a patient with early-onset atrial fibrillation (AF) in published literature (PMID: 34076677, 34495297); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24793961, 28005231, 23403236, 27600940, 22763267, 26332594, 24510615, 29300372, 18533079, 27483260, 21483645, 27247418, 27532257, 20215591, 19412328, 33179204, 34135346, 33087929, 32894683, 34363016, 30297972, 31517061, 34542152, 34495297, 36423990, 35653365, 34076677, 21832052) -

Hypertrophic cardiomyopathy

Pathogenic:2Uncertain:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1045 of the MYH7 protein (p.Arg1045Cys). This variant is present in population databases (rs45611033, gnomAD 0.01%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 26199943, 27247418, 27532257). ClinVar contains an entry for this variant (Variation ID: 177753). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg1045 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26199943, 27247418, 27532257). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Apr 15, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory -

Aug 25, 2021

ClinGen Cardiomyopathy Variant Curation Expert Panel

Significance:Uncertain significance

Review Status:reviewed by expert panel

Collection Method:curation

The NM_000257.4(MYH7):c.3133C>T (p.Arg1045Cys) variant has been identified in at least 12 individuals with HCM (PS4_Moderate; Olivotto 2008 PMID:18533079; Bos 2014 PMID:24793961; Homburger 2016 PMID:27247418; Rubattu 2016 PMID:27483260; Cecconi 2016 PMID:27600940; Walsh 2017 PMID: 27532257; Michels 2017 PMID:28005231) and in an additional individual with early-onset DCM that also carried a de novo TNNC1 variant (Hershberger 2008 PMID:19412328; Hershberger 2010 PMID:20215591; Rampersaud 2011 PMID:21483645; Pinto 2011; PMID:21832052). This variant was identified in 0.00152% (FAF 95% CI; 5/129168) of European chromosomes by gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate, PM2, PP3. -

Cardiomyopathy

Pathogenic:2

Apr 17, 2019

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 04, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces arginine with cysteine at codon 1045 in the neck and hinge (S2) domain of the MYH7 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in more than ten individuals affected with hypertrophic cardiomyopathy (PMID: 18533079, 24510615, 27247418, 27483260, 27532257, 27600940, 28005231, 32894683, 33495596, 33495597; ClinVar SCV000204029.4). This variant has been reported in one infant affected with dilated cardiomyopathy, who also carried a de novo variant in the TNNC1 gene, as well as in an unaffected parent (PMID: 21832052). This variant has also been reported in one additional individual affected with dilated cardiomyopathy (PMID: 37461109). This variant has been identified in 8/280246 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant at the same codon, p.Arg1045Leu, is considered to be disease-causing (ClinVar variation ID: 42948), indicating that arginine at this position is important for MYH7 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -

Hypertrophic cardiomyopathy 1

Pathogenic:2

Jun 11, 2020

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This c.3133C>T (p.Arg1045Cys) variant in the MYH7 gene has been reported in multiple individuals affected with hypertrophic cardiomyopathy (PMID 18533079, 24510615, 27247418, 27483260, 27532257, 27600940, 30297972). This variant is rare in the general population (8/282850 alleles in gnomAD). Two additional missense substitutions at this codon (p.Arg1045Leu, p.Arg1045His) have been reported in individuals affected with hypertrophic cardiomyopathy (PMID 26199943, 27247418, 27532257). In-silico predictions suggest a damaging effect of this variant. The c.3133C>T (p.Arg1045Cys) variant in the MYH7 gene is thus classified as likely pathogenic. -

Feb 23, 2023

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.93; 3Cnet: 0.38). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000177753) and different missense changes at the same codon (p.Arg1045His, p.Arg1045Leu / ClinVar ID: VCV000042948, VCV000651054) have been previously reported as pathogenic/likely pathogenic with strong evidence. The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 18533079, 24510615, 27532257, 30297972). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Primary familial hypertrophic cardiomyopathy

Pathogenic:1

Jun 23, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: MYH7 c.3133C>T (p.Arg1045Cys) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 2.4e-05 in 251472 control chromosomes. c.3133C>T has been observed in the heterozygous state in multiple individuals affected with Hypertrophic Cardiomyopathy (Kelly_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 29300372). ClinVar contains an entry for this variant (Variation ID: 177753). Based on the evidence outlined above, the variant was classified as pathogenic. -

MYH7-related disorder

Pathogenic:1

Feb 24, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The MYH7 c.3133C>T variant is predicted to result in the amino acid substitution p.Arg1045Cys. This variant was reported in multiple individuals with hypertrophic cardiomyopathy (Olivotto et al. 2008. PubMed ID: 18533079; Supplemental Table 1, Bos et al. 2014. PubMed ID: 24793961; Supplemental Dataset S1, Homburger et al. 2016. PubMed ID: 27247418; Lacaze et al. 2021. PubMed ID: 34135346). In addition, other missense variants resulting in a substitution at the p.Arg1045 residue (p.Arg1045His and p.Arg1045Leu) have also been reported in patients with hypertrophic cardiomyopathy (Supplementary Table S1B, Walsh et al. 2017. PubMed ID: 27532257; Supplemental Dataset S1, Homburger et al. 2016. PubMed ID: 27247418). This variant is reported in 0.0096% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-23891501-G-A). This variant is interpreted as likely pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Aug 14, 2024

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R1045C variant (also known as c.3133C>T), located in coding exon 23 of the MYH7 gene, results from a C to T substitution at nucleotide position 3133. The arginine at codon 1045 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in multiple individuals from hypertrophic cardiomyopathy cohorts (Olivotto I et al. Mayo Clin. Proc., 2008 Jun;83:630-8; Kapplinger JD et al. J Cardiovasc Transl Res, 2014 Apr;7:347-61; Rubattu S et al. Int J Mol Sci, 2016 Jul;17; Michels M et al. Neth Heart J, 2017 Mar;25:186-199; Walsh R et al. Genet. Med., 2017 02;19:192-203; Kelly MA et al. Genet Med, 2018 03;20:351-359). Another variant at the same codon, p.R1045L (c.3134G>T), has also been reported in association with HCM (Walsh R et al. Genet. Med., 2017 02;19:192-203). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

CardioboostCm

Uncertain

0.84

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.88

Eigen

Pathogenic

0.78

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.94

MetaRNN

Pathogenic

0.93

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.8

PhyloP100

3.9

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-6.2

REVEL

Pathogenic

0.93

Sift

Uncertain

0.0060

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.73

MVP

0.97

MPC

0.64

ClinPred

0.98

GERP RS

3.7

Varity_R

0.35

gMVP

0.92

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over