rs45611033

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3PS4_Moderate

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:10U:2

Conservation

PhyloP100: 3.93

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 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/exons	MANE	Protein	UniProt
MYH7	NM_000257.4 linkuse as main transcript	c.3133C>T	p.Arg1045Cys	missense_variant	25/40	ENST00000355349.4	NP_000248.2	P12883
MYH7	NM_001407004.1 linkuse as main transcript	c.3133C>T	p.Arg1045Cys	missense_variant	24/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4 linkuse as main transcript	c.3133C>T	p.Arg1045Cys	missense_variant	25/40	1	NM_000257.4	ENSP00000347507.3		P12883

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

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251472

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135912

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 SAS exome

AF:

0.0000327

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000441

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152286

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000980

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:10Uncertain:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 30, 2023	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) -
Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Dec 27, 2021	- -

Hypertrophic cardiomyopathy

Pathogenic:2Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 13, 2024	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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 15, 2020	proposed classification - variant undergoing re-assessment, contact laboratory -
Uncertain significance, reviewed by expert panel	curation	ClinGen Cardiomyopathy Variant Curation Expert Panel	Aug 25, 2021	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

Likely pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Apr 17, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 06, 2023	This missense variant replaces arginine with cysteine at codon 1045 in the neck and hinge (S2) domain of the MYH7 protein. Computational prediction suggests that this variant may have 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 over 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 an 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

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Jun 11, 2020	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. -

MYH7-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 24, 2023

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 14, 2024

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

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

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over