rs201865159

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP2PP3_Moderate

The NM_000257.4(MYH7):c.5494C>T(p.Arg1832Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000384 in 1,612,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1832H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:15

Conservation

PhyloP100: 4.08

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 3 ACMG points.

PP2

Missense variant where missense usually causes diseases, MYH7

PP3

MetaRNN computational evidence supports a deleterious effect, 0.917

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4 linkuse as main transcript	c.5494C>T	p.Arg1832Cys	missense_variant	37/40	ENST00000355349.4
MYH7	NM_001407004.1 linkuse as main transcript	c.5494C>T	p.Arg1832Cys	missense_variant	36/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4 linkuse as main transcript	c.5494C>T	p.Arg1832Cys	missense_variant	37/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152212

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:

0.00

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:

0.0000359

AC:

AN:

250790

Hom.:

AF XY:

0.0000369

AC XY:

AN XY:

135642

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000476

Gnomad NFE exome

AF:

0.0000616

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000397

AC:

AN:

1460736

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

726760

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000191

Gnomad4 NFE exome

AF:

0.0000459

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000281

Hom.:

Bravo

AF:

0.0000189

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:7

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 30, 2018	The R1832C variant of uncertain significance in the MYH7 gene has been reported previously in an adult male with personal and family history of idiopathic dilated cardiomyopathy (MÃ¸ller et al., 2009). Maron et al. (2012) reported this variant in conjunction with another variant in the MYBPC3 gene, in an adult male with personal and maternal family history of hypertrophic cardiomyopathy. Familial segregation analysis was not performed in either study. The R1832C variant was observed in 7/111,684 (0.006%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). R1832C is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Moreover, this substitution occurs at a position where only amino acids with similar properties to arginine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Although missense variants in nearby residues (E1829G, S1836L) have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014), the pathogenicity of these variants has not been definitively determined. Thus, this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 22, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 16, 2022	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 16, 2022	This missense variant replaces arginine with cysteine at codon 1832 of the MYH7 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 19293840) and in two siblings affected with skeletal myopathy and left ventricular non-compaction (Moore et al., 2018). This variant has been observed in an individual with hypertrophic cardiomyopathy, who also carried a pathogenic mutation in the MYBPC3 gene (PMID: 21839045). This variant has been identified in 9/250790 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	This missense variant replaces arginine with cysteine at codon 1832 of the MYH7 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 19293840) and in two siblings affected with skeletal myopathy and left ventricular non-compaction (Moore et al., 2018). This variant has been observed in an individual with hypertrophic cardiomyopathy, who also carried a pathogenic mutation in the MYBPC3 gene (PMID: 21839045). This variant has been identified in 9/250790 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Primary dilated cardiomyopathy

Uncertain:2

Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Uncertain significance, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Apr 05, 2018	- -

Dilated cardiomyopathy 1S;C3495498:Hypertrophic cardiomyopathy 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Nov 08, 2022

The c.5494C>T variant in MYH7 has previously been reported in one individual with idiopathic dilated cardiomyopathy [PMID: 19293840] and it has been deposited in ClinVar [ClinVar ID: 161322] as variant of uncertain significance by multiple submitters. The c.5494C>T variant is observed in 14 alleles (~0.002% minor allelefrequency with 0 homozygote) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases, which might include individuals with adult onset cardiac phenotypes. The c.5494C>T variant in MYH7 is located in exon 37 of this 40-exon gene, and is predicted to replace an evolutionarily conserved arginine amino acid with cysteine at position 1832 (p.(Arg1832Cys) in the C-terminalrod domain [PMID:35854315] of the encoded protein. In silico predictions provide supporting evidence for damaging effect for the p.(Arg1832Cys) variant [CADD v1.6= 27.4, REVEL = 0.767]; however, there are no functional studies to support or refute these predictions. Based on available evidence this c.5494C>Tp.(Arg1832Cys) variant identified in MYH7 is classified as a Variant of Uncertain Significance. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 17, 2021

- -

Hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 18, 2022

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1832 of the MYH7 protein (p.Arg1832Cys). This variant is present in population databases (rs201865159, gnomAD 0.006%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 19293840). ClinVar contains an entry for this variant (Variation ID: 161322). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 01, 2023

The p.R1832C variant (also known as c.5494C>T), located in coding exon 35 of the MYH7 gene, results from a C to T substitution at nucleotide position 5494. The arginine at codon 1832 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been detected in an individual with dilated cardiomyopathy (Møller DV et al. Eur J Hum Genet. 2009 Oct;17:1241-9), and in an individual with hypertrophic cardiomyopathy who also had a frameshift mutation in MYBPC3 (Maron BJ et al. Heart Rhythm. 2012 Jan;9:57-63). This variant has also been detected in exome cohorts. One individual with this variant from an exome cohort had a normal echocardiogram and ECG, while clinical details for other individuals were not provided (Andreasen C et al. Eur. J. Hum. Genet., 2013 Sep;21:918-28; Ng D et al. Circ Cardiovasc Genet. 2013 Aug;6(4):337-46). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

CardioboostCm

Uncertain

0.54

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.16

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Pathogenic

0.89

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.92

MetaSVM

Pathogenic

0.83

MutationAssessor

Pathogenic

4.1

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.52

PROVEAN

Pathogenic

-4.6

REVEL

Pathogenic

0.77

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.99

Vest4

0.62

MVP

0.98

MPC

1.8

ClinPred

0.99

GERP RS

4.3

Varity_R

0.44

gMVP

0.75

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