rs727503253

chr14-23424119-G-A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_000257.4(MYH7):c.2710C>T(p.Arg904Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R904H) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 0.265

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]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_000257.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-23424118-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 42926.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP2: Missense variant where missense usually causes diseases, MYH7
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.924
• PP5: Variant 14-23424119-G-A is Pathogenic according to our data. Variant chr14-23424119-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 164316.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr14-23424119-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4	c.2710C>T	p.Arg904Cys	missense_variant	23/40	ENST00000355349.4
MYH7	NM_001407004.1	c.2710C>T	p.Arg904Cys	missense_variant	22/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4	c.2710C>T	p.Arg904Cys	missense_variant	23/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251442 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135904

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461876 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

Submissions by phenotype

Primary dilated cardiomyopathy Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 19, 2018	The p.Arg904Cys variant in MYH7 has been identified in at least 4 individuals wi th DCM and segregated with disease in 11 affected relatives from 2 families (van der Zwaag 2011; Miller 2017; LMM data). It has also been identified in 1/9850 o f Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http: //gnomad.broadinstitute.org; dbSNP rs727503253). Arginine (Arg) at position 904 is highly conserved in mammals and across evolutionarily distant species and the change to cysteine (Cys) was predicted to be pathogenic using a computational t ool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). Of note, this variant li es in the head region of the protein. Missense variants in this region have been reported and statistically indicated to be more likely to cause disease (Walsh 2016). In summary, this variant meets criteria to be classified as pathogenic fo r dilated cardiomyopathy in an autosomal dominant manner based upon segregation studies, low frequency in controls, and predicted functional impact. ACMG/AMP Cr iteria applied: PP1_Strong; PM1; PM2; PP3; PS4_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 10, 2015	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Cardiomyopathy Variant Curation Expert Panel	Sep 27, 2021	The NM_000257.4:c.2710C>T (p.Arg904Cys) variant in MYH7 has been identified in 4 individuals with DCM in the literature (1 of whom also had LVNC; van Spaendonck-Zwarts 2013 PMID:23349452; van der Zwaag 2011 PMID:20573160; Walsh 2017 PMID:27532257; Miller 2017 PMID29212898) and 3 individuals with LVNC (2 of which were pediatric; Yang 2014 PMID:25326635; Wang 2017 PMID:28855170; van Waning 2018 PMID:29447731). This variant was identified in 8 individuals with DCM and 1 proband with LVNC by clinical laboratories (GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.; OMGL pers comm.). Only probands with DCM are counted towards PS4 (n=12; PS4_Moderate). This variant segregated with DCM in 15 affected individuals from 4 families (PP1_Strong; van der Zwaag 2011 PMID:20573160; GeneDx pers. comm.; LMM pers. comm.; OMGL pers. comm.) and was assumed de novo in 1 of the above cases (PM6; GeneDx pers. comm.). This variant has been identified in 0.010% (1/10080) of Ashkenazi Jewish chromosomes by gnomAD v2.1.1 (https://gnomad.broadinstitute.org), but was absent from all other populations. A different pathogenic missense variant has been previously identified at this codon, which indicates that this residue may be critical to the function of the protein (PM5; c.2711G>A p.Arg904His - Variation ID 42926). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate, PP1_Strong, PM6, PM2, PM5, PP3. -

Dilated cardiomyopathy 1S Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Feb 18, 2016	- -

Hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 20, 2024

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 904 of the MYH7 protein (p.Arg904Cys). This variant is present in population databases (rs727503253, gnomAD 0.01%). This missense change has been observed in individuals with dilated cardiomyopathy (PMID: 20573160, 23349452, 28855170, 29212898, 29447731; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 164316). 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.Arg904 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21750094, 22464770, 25448463; Invitae). 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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 09, 2020

The p.R904C pathogenic mutation (also known as c.2710C>T), located in coding exon 21 of the MYH7 gene, results from a C to T substitution at nucleotide position 2710. The arginine at codon 904 is replaced by cysteine, an amino acid with highly dissimilar properties and is located in the head (motor) domain of the protein. This variant was reported to segregate with disease in a large, multi-generational family with multiple members diagnosed with dilated cardiomyopathy (DCM) (van der Zwaag PA et al. Clin. Genet., 2011 May;79:459-67). Additionally, this variant has been reported in various cohorts of individuals diagnosed with DCM or left ventricular non-compaction (LVNC), however clinical data was limited (Wang C et al. J Am Heart Assoc, 2017 Aug;6(9); Miller EM et al. Circ Cardiovasc Genet, 2017 Dec;10(6); van Waning JI et al. J. Am. Coll. Cardiol., 2018 02;71:711-722). An alternate amino acid substitution at this position, p.R409H, has been reported in individual(s) with dilated cardiomyopathy (Waldmüller S et al. Eur. J. Heart Fail., 2011 Nov;13:1185-92). In addition to the clinical data presented in the literature, this amino acid position is highly conserved in available vertebrate species. Furthermore, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Hypertrophic cardiomyopathy 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Jul 24, 2019

The c.2710C>T variant in the MYH7 gene changes the arginine to a cysteine at codon 904 in the resultant protein (p.Arg904Cys). This codon lies within an important functional domain of MYH7 (amino acids 181-937). It is an evolutionarily conserved location and in-silico tools predict this change to be damaging. This particular variant has been reported in multiple individuals with dilated cardiomyopathy and segregates within families (PMID: 27532257, 20573160). In addition, a different missense substitution at this same codon (p.Arg904His) is considered pathogenic. It is an extremely rare variant having been seen in 1/251442 (0.000398%) individuals in gnomAD. According to ClinGen's Inherited Cardiomyopathy Expert Panel guidelines for interpretation of MYH7 (PMID: 29300372), this variant is considered pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.46		Loss of MoRF binding (P = 0.0469);
MVP		0.97
MPC		2.5
ClinPred		0.96	D
GERP RS		5.5
Varity_R		0.71
gMVP		0.99

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

Other links and lift over

dbSNP: rs727503253; hg19: chr14-23893328; COSMIC: COSV62516033;