Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000436727 | SCV000520770 | uncertain significance | not provided | 2016-12-19 | criteria provided, single submitter | clinical testing | The T171M variant of uncertain significance in the CACNA1C gene has been reported in one individual with sudden unexplained death who also harbored a variant in the MYH7 gene (Narula et al., 2015). This variant was not observed with any significant frequency in the Exome Aggregation Consortium or in approximately 5,900 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The T171M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, no missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with disease (Stenson et al., 2014).Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. This result cannot be interpreted for diagnosis or used for family member screening at this time. |
Invitae | RCV000804628 | SCV000944545 | uncertain significance | Long QT syndrome | 2021-09-07 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine with methionine at codon 171 of the CACNA1C protein (p.Thr171Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs199586997, ExAC 0.02%). This missense change has been observed in individual(s) with clinical features of CACNA1C-related conditions (PMID: 25500949). ClinVar contains an entry for this variant (Variation ID: 381482). 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"). 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. |
Ambry Genetics | RCV002339007 | SCV002642258 | uncertain significance | Cardiovascular phenotype | 2021-09-10 | criteria provided, single submitter | clinical testing | The p.T171M variant (also known as c.512C>T), located in coding exon 4 of the CACNA1C gene, results from a C to T substitution at nucleotide position 512. The threonine at codon 171 is replaced by methionine, an amino acid with similar properties. This variant has been detected in an individual with sudden death who also had a variant in another cardiac-related gene (Narula N et al. Pediatr Cardiol, 2015 Apr;36:768-78). 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. |
Fulgent Genetics, |
RCV002506030 | SCV002815222 | uncertain significance | Timothy syndrome; Brugada syndrome 3; Long qt syndrome 8 | 2021-09-30 | criteria provided, single submitter | clinical testing |