Submissions for variant NM_000257.4(MYH7):c.5452C>T (p.Arg1818Trp)

gnomAD frequency: 0.00001  dbSNP: rs763073072

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000804452	SCV000256635	uncertain significance	Hypertrophic cardiomyopathy	2019-01-18	criteria provided, single submitter	research	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'.
Eurofins Ntd Llc (ga)	RCV000484117	SCV000344617	uncertain significance	not provided	2016-08-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000484117	SCV000565294	uncertain significance	not provided	2021-03-16	criteria provided, single submitter	clinical testing	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)
Invitae	RCV000804452	SCV000944363	uncertain significance	Hypertrophic cardiomyopathy	2023-07-18	criteria provided, single submitter	clinical testing	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).
Ambry Genetics	RCV002345720	SCV002652297	uncertain significance	Cardiovascular phenotype	2019-08-19	criteria provided, single submitter	clinical testing	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.
Fulgent Genetics, Fulgent Genetics	RCV002478719	SCV002780328	uncertain significance	Hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; MYH7-related skeletal myopathy	2021-11-14	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997038	SCV004828142	uncertain significance	Cardiomyopathy	2024-01-11	criteria provided, single submitter	clinical testing	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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000223714	SCV000280367	uncertain significance	not specified	2012-05-30	no assertion criteria provided	clinical testing	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 no variation at this residue listed in dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP) or 1000 Genomes (http://browser.1000genomes.org/index.htm) as of 1/26/2015. It is not present in ClinVar http://www.ncbi.nlm.nih.gov/clinvar/. Our patient’s ancestry is Mexican (predominantly), Caucasian, and some African-American. Ancestry-matched individuals can be found in greater numbers in the ExAC database of 60,000 exomes from disease-specific and population genetic studies (with efforts made to exclude individuals with severe pediatric diseases). ExAC currently contains 5778 “Latino” individuals. There are 2 individuals in ExAc with this variant and both of them are Latino. It is not present in the other ethnicities (African, South Asian, East Asian, Caucasian) represented in ExAC.