rs45544633

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM5PP2PP3_StrongPP5_Very_Strong

The NM_000257.4(MYH7):c.4498C>T(p.Arg1500Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,892 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1500P) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 0.238

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:

MHRT (HGNC:):

MHRT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr14-23417173-C-G is described in Lovd as [Pathogenic].

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYH7. . Gene score misZ 3.9329 (greater than the threshold 3.09). Trascript score misZ 6.7889 (greater than threshold 3.09). GenCC has associacion of gene with hyaline body myopathy, MYH7-related skeletal myopathy, dilated cardiomyopathy 1S, congenital myopathy 7A, myosin storage, autosomal dominant, dilated cardiomyopathy, left ventricular noncompaction, myopathy, myosin storage, autosomal dominant, hypertrophic cardiomyopathy, congenital heart disease, Ebstein anomaly, arrhythmogenic right ventricular cardiomyopathy, myopathy, myosin storage, autosomal recessive, hypertrophic cardiomyopathy 1, familial isolated dilated cardiomyopathy.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.952

PP5

Variant 14-23417174-G-A is Pathogenic according to our data. Variant chr14-23417174-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 164284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23417174-G-A is described in Lovd as [Pathogenic]. Variant chr14-23417174-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MYH7	NM_000257.4 linkuse as main transcript	c.4498C>T	p.Arg1500Trp	missense_variant	32/40	ENST00000355349.4	NP_000248.2
MHRT	NR_126491.1 linkuse as main transcript	n.652-38G>A		intron_variant, non_coding_transcript_variant
MYH7	NM_001407004.1 linkuse as main transcript	c.4498C>T	p.Arg1500Trp	missense_variant	31/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4 linkuse as main transcript	c.4498C>T	p.Arg1500Trp	missense_variant	32/40	1	NM_000257.4	ENSP00000347507	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cardiomyopathy

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jun 12, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 22, 2022	This missense variant replaces arginine with tryptophan at codon 1500 in the LMM domain in the C-terminal tail region of the MYH7 protein that forms the thick filament backbone and interacts with other proteins. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). In vitro functional studies provide some evidence that this variant may destabilize the MYH7 protein (PMID: 19854198, 22155079, 24047955). This variant has been reported in more than 10 individuals affected with dilated cardiomyopathy (PMID: 15556047, 18660445, 24119082, 26383716, 28750076, 31317183; communication with external laboratories: ClinVar SCV000901918.1 and SCV000737223.3) and in multiple individuals with left ventricular noncompaction cardiomyopathy (communication with external laboratories: ClinVar SCV000199112.4 and SCV000737223.3). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Primary dilated cardiomyopathy

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 29, 2017	The p.Arg1500Trp variant in MYH7 has been reported in the heterozygous state in 2 adults with LVNC and at least 6 adults with DCM (Karkkainen 2004, Jerosch-Hero l 2008, Merlo 2013, Hazebroek 2015, ClinVar Variation ID 164284). It was also id entified in the homozygous state in 1 child with neonatal DCM (GeneDx personal c ommunication). Furthermore, the variant segregated with disease in 2 affected re latives from 1 family (Jerosch-Herol 2008) and was absent from large population studies. In vitro functional studies provide some evidence that the p.Arg1500Trp variant may impact protein function (Armel 2010, Wolny 2013). However, these ty pes of assays may not accurately represent biological function. Additionally, th is variant was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to b e correct 94% of the time (Jordan 2011). In summary, although additional studies are required to fully establish its clinical significance, the p.Arg1500Trp var iant is likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 15, 2023	The c.4498C>T (p.Arg1500Trp) variant in MYH7 gene, that encodes for myosin heavy chain 7, has been identified in at least seven unrelated individuals affected with Dilated Cardiomyopathy (DCM) (PMID:15556047, 19412328, 24119082, 28750076, 26383716, 32880476, 29540472). This variant is found to segregate with three affected individuals including the proband in one family (PMID: 18660445). Experimental studies have shown that this missense change causes severely decreased thermodynamic stability and affects filament assembly (PMID: 19854198). However, other studies have shown that this variant doesn?t appreciably affect myosin filament formation, myosin heavy chain incorporation into muscle sarcomeres, and myocyte contraction (PMID: 22155079, 24047955). In-silico computational prediction tools suggest that this variant may have deleterious effect on the protein function (REVEL score: 0.836). This variant is found to be absent in the general population database (gnomAD) and interpreted as likely pathogenic by multiple submitters in the ClinVar database (ClinVar ID: 164284). Therefore, the c.4498C>T (p.Arg1500Trp) variant in the MYH7 gene is classified as likely pathogenic. -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 18, 2021

- -

not provided

Pathogenic:1

Likely pathogenic, no assertion criteria provided

provider interpretation

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Jan 11, 2016

- -

Hypertrophic cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 27, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1500 of the MYH7 protein (p.Arg1500Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant dilated cardiomyopathy (PMID: 15556047, 18660445, 19412328, 24119082). ClinVar contains an entry for this variant (Variation ID: 164284). 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%. Experimental studies have shown that this missense change affects MYH7 function (PMID: 19854198). This variant disrupts the p.Arg1500 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15322983, 19854198, 22155079). 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. -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 21, 2024

The p.R1500W variant (also known as c.4498C>T), located in coding exon 30 of the MYH7 gene, results from a C to T substitution at nucleotide position 4498. The arginine at codon 1500 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in several dilated cardiomyopathy (DCM) cohorts (Kärkkäinen S et al. Eur. J. Heart Fail. 2004;6:861-8; Hershberger RE et al. Clin Transl Sci. 2008;1:21-6; Jerosch-Herold M et al. Am. J. Physiol. Heart Circ. Physiol. 2008;295:H1234-H1242; Merlo M et al. Clin Transl Sci. 2013;6:424-8; Forleo C et al. PLoS ONE. 2017;12:e0181842). In vitro studies suggest that this alteration has an impact on filament formation; however, the same effect was not reproduced in vivo (Armel TZ et al. J. Mol. Cell. Cardiol., 2010 May;48:1007-13; Buvoli M et al. J. Mol. Biol. 2012;415:807-18; Wolny M et al. J. Biol. Chem., 2013 Nov;288:31952-62). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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

Pathogenic

0.85

CardioboostCm

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.31

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.91

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.92

M_CAP

Pathogenic

0.93

MetaRNN

Pathogenic

0.95

MetaSVM

Pathogenic

0.91

MutationAssessor

Pathogenic

4.4

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-6.0

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.97

MutPred

0.65

Loss of methylation at K1499 (P = 0.0452);

MVP

0.90

MPC

1.4

ClinPred

1.0

GERP RS

0.85

Varity_R

0.70

gMVP

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

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