rs763073072

chr14-23415102-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP2 PP3_Moderate

The NM_000257.4(MYH7):c.5452C>T(p.Arg1818Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,686 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. R1818Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8
• Conservation: PhyloP100: 2.83

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 Uncertain_significance. Variant got 3 ACMG points.

• PP2: Missense variant where missense usually causes diseases, MYH7
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.912

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4	c.5452C>T	p.Arg1818Trp	missense_variant	37/40	ENST00000355349.4
MYH7	NM_001407004.1	c.5452C>T	p.Arg1818Trp	missense_variant	36/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4	c.5452C>T	p.Arg1818Trp	missense_variant	37/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251394 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135890

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

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: 0.00000547 AC: 8 AN: 1461686 Hom.: 0 Cov.: 34 AF XY: 0.00000688 AC XY: 5 AN XY: 727154

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 16, 2021	Reported in association with hypertrophic cardiomyopathy; however, the R1818W variant did not segregate with disease in one family (Berge et al., 2014; Burns et al., 2017); Reported in ClinVar (ClinVar Variant ID# 217826; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 24111713, 28971120, 28790153) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 18, 2016	- -

Hypertrophic cardiomyopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	Jan 18, 2019	MYH7 Arg1818Trp has been reported in 2 HCM probands (Berge & Leren, 2014; Gomez et al., 2014). We have also identified this variant in a single HCM proband who presented with asymmetric hypertrophy (IVS 16mm) and also carries a second MYH7 variant (Asp778Val) in trans with MYH7 Arg1818Trp (Ingles et al., 2017). A deceased family member was diagnosed with HCM at post-mortem (max IVS= 34mm) and only the MYH7 Asp778Val variant was found to segregate in this individual. GeneDx report this variant in 1 DCM proband who harboured additional variants in RYR2 and DSG2, furthermore they found the variant did not segregate to an affected relative (Pers. Comm.) The variant is present in the Genome Aggregation Database (http://gnomad.broadinstitute.org/), at an allele frequency of 0.0000081. In silico tools SIFT, PolyPhen-2, PolyPhen-HCM and MutationTaster predict this variant to be deleterious. Based on the adapted ACMG criteria (Kelly MA, et al., 2018) this variant is rare in the general population (PM2), is predicted to be deleterious by multiple in silico tools (PP3), has been reported in at least 2 HCM probands, without additional plausible variants (PS4_Supporting), however in 2 cases the variant was found alongside other suspicious variants and did not segregate to an affected family member, therefore we classify MYH7 Arg181Trp as a variant of 'uncertain significance'. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 18, 2023	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. 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. ClinVar contains an entry for this variant (Variation ID: 217826). This missense change has been observed in individual(s) with personal and/or family history of hypertrophic cardiomyopathy (PMID: 24111713, 28356264, 28790153, 28971120). This variant is present in population databases (rs763073072, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1818 of the MYH7 protein (p.Arg1818Trp). -

not specified Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Stanford Center for Inherited Cardiovascular Disease, Stanford University

May 30, 2012

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. This patient is a is a 16-year old male with a history of multiple syncopal episodes, and a diagnosis of intermittent complete AV block including a 5.6 second asystolic pause on event monitor, who is now s/p pacemaker placement. GENETIC TEST RESULTS: The patient had genetic testing through the Fulgent Diagnostics laboratory. This consisted of their 103-gene Pan-Cardio sequencing panel with gene TRPM4 added, and with deletion/duplication testing requested for all genes: ABCC9, ACTC1, ACTN2, AKAP9, ANK2, ANKRD1, APOA5, BAG3, CACNA1C, CACNA2D1, CACNB2, CALR3, CASQ2, CAV3, COX15, CRYAB, CSRP3, CTF1, DES, DMD, DOLK, DSC2, DSG2, DSP, DTNA, EMD, EYA4, FKTN, FLNA, FXN, GAA, GATA4, GATAD1, GJA5, GLA, GPD1L, HCN4, ILK, JAG1, JPH2, JUP, KCNA5, KCNE1, KCNE2, KCNE3, KCNH2, KCNJ2, KCNJ5, KCNJ8, KCNQ1, LAMA4, LAMP2, LDB3, LDLR, LMNA, MRPL3, MURC, MYBPC3, MYH6, MYH7, MYL2, MYL3, MYLK2, MYOM1, MYOZ2, MYPN, NDUFAF1, NEBL, NEXN, NKX2-5, NPPA, PDLIM3, PKP2, PLN, PRKAG2, PSEN2, PTPN11, RAF1, RBM20, RYR2, SCN1B, SCN3B, SCN4B, SCN5A, SDHA, SGCD, SNTA1, SYNE1, TAZ, TBX1, TBX5, TCAP, TGFB3, TMEM43, TMPO, TNNC1, TNNI3, TNNT2, TPM1, TRPM4, TTN, TTR, TXNRD2, VCL. Results reported on 1/9/2015 show that two variants of unknown clinical significance were identified in the DSG2 and MYH7 genes: 1) p.Arg146Leu (p.R146L; c.437G>T) in the DSG2 gene 2) p.Arg1818Trp (p.R1818W; c.5452C>T) in the MYH7 gene p.Arg146Leu (p.R146L; c.437G>T) in exon 5 of the DSG2 gene (NM_001943.3) Fulgent classifies p.Arg146Leu as a variant of unknown clinical significance. Based on the information reviewed below, we too classify it as a variant of unknown significance. There is not enough confidence in the p.Arg146Leu variant to use it for predictive genetic testing in at-risk family members. DSG2 is a gene typically associated with arrhythmogenic right ventricular cardiomyopathy (ARVC). Of note, Kapplinger et al. (2011) from Dr. Michael Ackerman’s group at Mayo Clinic have reported a significant yield of rare missense variants in the ARVC genes of presumably healthy controls from various ethnicities. According to their data, p.Arg1818Trp (p.R1818W; c.5452C>T) in exon 37 of the MYH7 gene (NM_000257.2) Based on the information reviewed below, we too classify it as a variant of uncertain significance, concluding that there is not sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing. This variant has not been reported in the literature in association with disease. This is a non-conservative amino acid change, resulting in the replacement of a positively-charged Arginine with a nonpolar Tryptophan. The Arginine at this location is highly conserved across mammalian species, although it is a Glutamine or Lysine in a few. The adjacent residues are also highly conserved. Variation at a nearby residue (+/- 10) has been associated with hypertrophic or dilated cardiomyopathy, which may support the functional importance of this region of the protein: Gly1808Ser, Gly1808Ala (HGMD professional version as of January 17, 2014). In total the variant has been seen in 2 out of over 60,000 published controls and individuals from publicly available population datasets. There is no variation at this residue listed in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals. The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. There is also -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jan 11, 2024

This missense variant replaces arginine with tryptophan at codon 1818 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 individuals affected with hypertrophic cardiomyopathy (PMID: 24111713, 28356264, 28408708, 28790153, 28971120, 30327538). One of these individuals also carried an additional variant in the MYH7 gene (PMID: 28408708, 28790153, 30327538). This variant has been identified in 2/251394 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. -

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 14, 2021

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 19, 2019

The p.R1818W variant (also known as c.5452C>T), located in coding exon 35 of the MYH7 gene, results from a C to T substitution at nucleotide position 5452. The arginine at codon 1818 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in several hypertrophic cardiomyopathy (HCM) cohorts; however, clinical data was limited (Berge KE and TP Leren. Clin Genet. 2014;86(4):355-60; Gómez J et al. Circ Cardiovasc Genet, 2017 Apr;10:e001584). This variant has also been detected in a proband with HCM who was heterozygous for a second alteration in MYH7 (Burns C et al. Circ Cardiovasc Genet, 2017 Aug;10:e001666). 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	Pathogenic	0.82
CardioboostCm	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.18
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	4.2	H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.50		Gain of catalytic residue at R1818 (P = 0.0117);
MVP		0.97
MPC		1.6
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.45
gMVP		0.96

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: rs763073072; hg19: chr14-23884311; COSMIC: COSV62520208; COSMIC: COSV62520208;