ClinVar Genomic variation as it relates to human health

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.

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"). This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). 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. ClinVar contains an entry for this variant (Variation ID: 177858). This variant has not been reported in the literature in individuals affected with MYH7-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with valine at codon 233 of the MYH7 protein (p.Ala233Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine.

The p.A233V variant (also known as c.698C>T), located in coding exon 6 of the MYH7 gene, results from a C to T substitution at nucleotide position 698. The alanine at codon 233 is replaced by valine, an amino acid with similar properties. This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). Another alteration at the same amino acid position, p.A233S, has been reported in individuals with hypertrophic cardiomyopathy (HCM) (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6).This amino acid position is highly 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.

proposed classification - variant undergoing re-assessment, contact laboratory

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.