ClinVar Miner

Submissions for variant NM_003803.3(MYOM1):c.2086C>T (p.Arg696Cys) (rs757565820)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000547613 SCV000623829 uncertain significance Hypertrophic cardiomyopathy 2018-05-29 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 696 of the MYOM1 protein (p.Arg696Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs757565820, ExAC 0.006%). This variant has not been reported in the literature in individuals with MYOM1-related disease. ClinVar contains an entry for this variant (Variation ID: 454435). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000786374 SCV000925182 uncertain significance not provided 2017-05-30 no assertion criteria provided provider interpretation This patient is a 14-year old female with a history of chronic dizziness and one episode of VT detected on Holter. She had an Arrhythmia and Cardiomyopathy Comprehensive Panel with the Invitae Laboratory. The following genes were evaluated for sequence changes and exonic deletions/duplications: ABCC9, ACTC1, ACTN2, AGL, AKAP9, ANK2, ANKRD1, BAG3, CACNA1C, CACNA2D1, CACNB2, CALM1, CALM2, CALM3, CALR3, CASQ2, CAV3, CHRM2, CRYAB, CSRP3, CTF1, CTNNA3, DES, DMD, DOLK, DSC2, DSG2, DSP, DTNA, EMD, EYA4, FHL1, FHL2, FKRP, FKTN, FLNC, GAA, GATA4, GATA6, GATAD1, GJA5, GLA, GPD1L, HCN4, ILK, JPH2, JUP, KCNA5, KCND3, KCNE1, KCNE2, KCNE3, KCNE5, KCNH2, KCNJ2, KCNJ5, KCNJ8, KCNK3, KCNQ1, LAMA4, LAMP2, LDB3, LMNA, LRRC10, MYBPC3, MYH6, MYH7, MYL2, MYL3, MYL4, MYLK2, MYOM1, MYOZ2, MYPN, NEBL, NEXN, NKX2-5, NPPA, PDLIM3, PKP2, PLEKHM2, PLN, PRDM16, PRKAG2, RAF1, RANGRF, RBM20, RYR2, SCN10A, SCN1B, SCN2B, SCN3B, SCN4B, SCN5A, SGCD, SLC22A5, SLMAP, SNTA1, TAZ, TCAP, TGFB3, TMEM43, TMPO, TNNC1, TNNI3, TNNT2, TPM1, TRDN, TRPM4, TTN, TTR, TXNRD2, VCL. Results indicate that two variants were detected: p.Asp123Asn (D123N; c.367G>A) in the TRDN gene p.Arg696Cys (c.2086C>T) in the MYOM1 gene We do not currently suspect that either of these is the cause of her episodes of dizziness and VT. p.Arg696Cys (R696C; c.2086C>T) in exon 15 of the MYOM1 gene (NM_003803.3) Chromosome position 18:3135668 G / A The MYOM1 gene has no well-established disease connection, but preliminary evidence associates it with autosomal dominant HCM. Invitae classifies Arg696Cys as a Variant of Uncertain Significance (VUS). It has not been reported to ClinVar as of 5/22/2017. Based on the information reviewed below, we classify it as a VUS as well, concluding that there is not sufficient evidence for its pathogenicity to warrant using it for diagnosis or predictive genetic testing. This variant has not previously been reported in the literature in association with disease. This is a nonconservative amino acid change, resulting in the replacement of a positively-charged Arginine with a polar Cysteine capable of forming disulfide bonds. Arginine at this location is highly conserved across ~100 vertebrate species for which we have data, although it is a Histidine in at least 2 species. There is currently no missense variation at nearby residues (+/- 10 amino acids) listed in ClinVar as Likely Pathogenic or Pathogenic. According to the Invitae report, algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant was reported in 6/123,074 individuals with exomes in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Specifically, the variant was observed in 2/15,388 South Asian individuals (for the highest allele frequency: 0.0065%), and 4 European non-Finnish individuals for allele frequency 0.0035%. Overall variant frequency 0.002%. Of note, gnomAD also contains 59 individuals with a different change at this same codon, Arg696His (highest allele frequency 0.186% in East Asian individuals), and 4 individuals with Arg696Leu. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases. Our patient’s ancestry is Caucasian and Vietnamese.

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