ClinVar Miner

Submissions for variant NM_000257.3(MYH7):c.5452C>T (p.Arg1818Trp) (rs763073072)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000201909 SCV000256635 uncertain significance Familial hypertrophic cardiomyopathy 1 2015-07-30 criteria provided, single submitter research The MYH7 Arg1818Trp variant has been reported by Berge et al (2013) in 1 HCM patient however phenotype data was not available. This variant has been reported with an allele frequency of 0.00001 (2/121,392 European non-Finnish alleles) in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). The MYH7 Arg1818Trp variant occurs in a conserved region, and in-silico tools (SIFT, PolyPhen, MutationTaster and CADD) support a damaging role for this variant, however this alone is not strong evidence for pathogenicity. We have identified this variant in a single HCM proband who presented with asymmetric hypertrophy (IVS 16mm). This proband also carries a likely pathogenic MYH7 variant in trans with this MYH7 Arg1818Trp. Based on our finding in an isolated HCM case who carries an additional variant, and limited reports in the literature, we have classified this variant as having "uncertain significance". Additional evidence is required to fully establish its pathogenic role.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000484117 SCV000344617 uncertain significance not provided 2016-08-18 criteria provided, single submitter clinical testing
GeneDx RCV000484117 SCV000565294 likely pathogenic not provided 2015-01-28 criteria provided, single submitter clinical testing A variant that is likely pathogenic was identified in the MYH7 gene. R1818W has been reported in one individual referred for HCM genetic testing, however, clinical information, family history and segregation data were not provided (Berge & Leren, 2014). Nevertheless, the R1818W variant was not observed in approximately 6500 individuals of European and African American ancestry in an external variant database, indicating it is not a common benign variant in these populations. The R1818W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, missense variants in nearby residues (G1808A, G1808S, E1829G) have been reported in the Human Gene Mutation Database in association with HCM (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded.
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.

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