Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000844680 | SCV000059226 | pathogenic | Hypertrophic cardiomyopathy | 2012-02-13 | criteria provided, single submitter | clinical testing | The Tyr1100fs variant (MYBPC3) has not been reported in the literature but has b een identified in one individual with HCM (this individual's father) by our labo ratory. This frameshift variant is predicted to alter the protein?s amino acid sequence beginning at position 1100 and lead to a premature termination codon 49 amino acids downstream. This alteration is then predicted to lead to a truncate d or absent protein. Heterozygous loss of function of the MYBPC3 gene is an esta blished disease mechanism in HCM, which makes it highly likely that this variant is pathogenic. |
| Blueprint Genetics | RCV000223806 | SCV000928090 | pathogenic | not provided | 2018-11-30 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000844680 | SCV001201680 | pathogenic | Hypertrophic cardiomyopathy | 2023-11-12 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Tyr1100Valfs*49) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This variant is present in population databases (rs397516014, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 42702). For these reasons, this variant has been classified as Pathogenic. |
| Stanford Center for Inherited Cardiovascular Disease, |
RCV000223806 | SCV000280259 | likely pathogenic | not provided | 2013-08-29 | 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. p.Tyr1100ValfsX49 (c. 3297dupG) in the MYBPC3 gene. We classify it as likely disease causing, based on the data reviewed below. The variant was re-reviewed February 17th, 2012. This variant is novel. The addition of Guanine at position 3297 causes a reading frame shift at codon 1100; as a result a premature stop codon is created 49 codons downstream. The amino acid sequence from codon 1100 to 1149 is changed, as well. The variant is expected to either cause a truncated MYBPC3 protein or a completely absent MYBPC3 protein due to nonsense-mediate mRNA decay. While this specific variant is novel, many other frameshift and null variants have been identified in MYBPC3 in association with cardiomyopathy (ex. p.Trp792fs, p.Pro794fs, p.Lys1065fs, p.Cys1202fs, p.Pro1208fs, p.Trp1098ter, p.Glu1096ter, p.Cys1124ter, p.Gln1233ter). The variant has not been seen in a total of 5200 laboratory controls and publicly available general population samples. The variant is not listed in the NHLBI Exome Sequencing Project dataset, which currently includes calls for MYBPC3 on ~5000 Caucasian and African-American individuals. Of note, there are no frameshift variants in that dataset. These if one nonsense variant, but it has been reported previously in association with HCM. There was no control data reported in the results. Upon request, GeneDx verbally provided control data on March 31st, 2011; the variant was not observed in 100 Caucasian control individuals (with high coverage) or 100 African American control individuals (with low coverage). |