ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.698C>T (p.Ala233Val) (rs727504362)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766410 SCV000208813 uncertain significance not provided 2015-10-14 criteria provided, single submitter clinical testing Although the A233V variant has not been reported as a pathogenic variant or a benign variant, to our knowledge, it has previously been identified in one other individual who underwent genetic testing for cardiomyopathy . This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Missense variants in nearby residues (A223T, L227V, N232S, T235N, V236I, D239N, R243C, R243H) including a different missense variant at the same residue (A233S) have been reported in HGMD in association with cardiomyopathy (Stenson et al., 2014), supporting the functional importance of this residue and region of the protein. This substitution occurs at a position that is conserved across species. However, the A233V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000154496 SCV000204166 uncertain significance not specified 2014-01-17 no assertion criteria provided clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000766410 SCV000924870 uncertain significance not provided 2017-10-11 no assertion criteria provided provider interpretation Found in a pediatric patient with LVNC who had a Comprehensive Cardiomyopathy Panel with the GeneDx laboratory. The test included sequencing of 76 genes and additional deletion/duplication analysis of 60 of those genes (nuclear genes) associated with various forms of cardiomyopathy: ABCC9 , ACTC (ACTC1), ACTN2, ANKRD1, BAG3 , BRAF, CAV3, CRYAB , CSRP3, DES, DMD, DSC2, DSG2, DSP, DTNA, EMD, FKTN, GATAD1, GLA, HRAS, ILK, JPH2, JUP, KRAS, LAMA4, LAMP2, LDB3 (ZASP), LMNA, MAP2K1, MAP2K2, MTND1, MTND5, MTND6, MTTD, MTTG, MTTH, MTTI, MTTK, MTTL1, MTTL2, MTTM, MTTQ, MTTS1, MTTS2, MYBPC3, MYH7, MYL2, MYL3, MYLK2, MYOZ2, MYPN, NEBL , NEXN, NRAS, PDLIM3, PKP2, PLN, PRKAG2, PTPN11, RAF1, RBM20, RYR2, SCN5A, SGCD, SOS1, TAZ, TCAP, TMEM43, TMPO, TNNC1, TNNI3, TNNT2, TPM1, TTN, TTR, VCL. Results show that 2 variants were detected: • p.Glu561_Glu562del (c.1677_1682delGGAGGA) in the NEXN gene - which we consider likely to be benign because it is 10x more frequent in patients with African ancestry such as this patient • p.Ala233Val (c.698C>T) in the MYH7 gene p.Ala233Val (c.698C>T) in exon 8 of the MYH7 gene Chromosome location 14:23900828 G / A Based on the data reviewed below we consider this to be a Variant of Uncertain Significance, but still consider it a good candidate to be disease-causing. More data is required to understand its clinical significance. This variant has not been reported in the literature in association with disease, to the best of our knowledge. Girolami et al. (2006) reported a different variant at the same residue, Ala233Ser, in an Italian patient with hypertrophic cardiomyopathy. This is a conservative amino acid change, resulting in the replacement of a nonpolar Alanine with a nonpolar Valine. Alanine at this location is absolutely conserved across ~100 vertebrate species for which we have data. The adjacent residues are also highly conserved. Missense variants at nearby residues (+/- 10 amino acids), including a different missense variant at the same residue (Ala233Ser), have been reported in ClinVar as Likely Pathogenic or Pathogenic: Arg243His, Asp239Asn, Arg237Trp, Ala233Ser, Ala226Val, Ala226Thr. This supports the functional importance of this region of the protein. The variant is in the head of myosin, which is enriched for pathogenic variation. Specifically, it is in the ATP-binding domain. In silico prediction models are not in agreement regarding this variant. Analysis with Mutation Taster considers it “disease causing” while PolyPhen-2 predicts that it is "benign." There is no variation at this residue reported in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. There is good coverage at this site. 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.

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