Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002422058 | SCV002725177 | uncertain significance | Cardiovascular phenotype | 2021-01-29 | criteria provided, single submitter | clinical testing | The c.2067G>T variant (also known as p.Q689H), located in coding exon 21 of the MYBPC3 gene, results from a G to T substitution at nucleotide position 2067. The glutamine at codon 689 is replaced by histidine, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 21, which makes it likely to have some effect on normal mRNA splicing. This variant was detected in an individual with a clinical diagnosis of hypertrophic cardiomyopathy (HCM) and in four of this individual's relatives; two relatives had cardiac findings and two were unaffected (Brion M et al. Ann Clin Lab Sci, 2010;40:285-9). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. In addition, as a missense substitution this is predicted to be inconclusive by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Labcorp Genetics |
RCV003098592 | SCV003439734 | uncertain significance | Hypertrophic cardiomyopathy | 2022-07-19 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 689 of the MYBPC3 protein (p.Gln689His). This variant also falls at the last nucleotide of exon 21, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 20689143, 20800588). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. |