rs45544633

Positions:

• chr14-23417174-G-A
• chr14-23417174-G-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM5 PP2 PP3_Strong PP5_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. R1500Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 0.238

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]

MHRT (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000257.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-23417173-C-T is described in ClinVar as [Uncertain_significance]. Clinvar id is 180439.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=4, Likely_pathogenic=2}.
• PP2: Missense variant where missense usually causes diseases, MYH7
• 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	UniProt
MYH7	NM_000257.4	c.4498C>T	p.Arg1500Trp	missense_variant	32/40	ENST00000355349.4
MHRT	NR_126491.1	n.652-38G>A		intron_variant, non_coding_transcript_variant
MYH7	NM_001407004.1	c.4498C>T	p.Arg1500Trp	missense_variant	31/39

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461892 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

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.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

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	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. -
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. -

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

Invitae

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	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	4.4	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.0	D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.65		Loss of methylation at K1499 (P = 0.0452);
MVP		0.90
MPC		1.4
ClinPred		1.0	D
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

Other links and lift over

dbSNP: rs45544633; hg19: chr14-23886383; COSMIC: COSV62516913; COSMIC: COSV62516913;