Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000035448 | SCV000059096 | pathogenic | Hypertrophic cardiomyopathy | 2011-12-27 | criteria provided, single submitter | clinical testing | The Phe631fs variant has not been previously reported, but has been identified i n 1 individual with HCM out of >1950 Caucasian probands (>3900 chromosomes) test ed by our laboratory. This low frequency is consistent with a pathogenic role. T his variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 631 and leads to a premature stop codon 32 ami no acids downstream. This alteration is then predicted to lead to a truncated or absent protein (loss-of-function). Loss-of-function of the MYBPC gene is an est ablished disease mechanism and typically leads to HCM, which is consistent with the phenotype of the proband tested by our laboratory. Therefore, this variant m eets our criteria for pathogenicity based on low frequency and predicted impact on the protein (http://pcpgm.partners.org/LMM). |
| Gene |
RCV000520707 | SCV000617254 | pathogenic | not provided | 2017-09-06 | criteria provided, single submitter | clinical testing | The c.1892delT pathogenic variant in the MYBPC3 gene has been reported in association with hypertrophic cardiomyopathy (HCM) (Ho et al., 2017; Walsh et al., 2017). Furthermore, this variant has been classified as a pathogenic variant by another clinical laboratory in ClinVar (SCV000059096.4; Landrum et al., 2016). This variant causes a shift in reading frame starting at codon phenylalanine 631, changing it to a serine, and creating a premature stop codon at position 32 of the new reading frame, denoted p.Phe631SerfsX32. This pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other frameshift variants in the MYBPC3 gene have been reported in Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014), indicating that loss of function is a mechanism of disease for this gene. Furthermore, the c.1892delT variant has not been observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). |