Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000132372 | SCV000187462 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-12-29 | criteria provided, single submitter | clinical testing | The p.P146T variant (also known as c.436C>A), located in coding exon 6 of the SDHC gene, results from a C to A substitution at nucleotide position 436. The proline at codon 146 is replaced by threonine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Labcorp Genetics |
RCV000534423 | SCV000641443 | uncertain significance | Gastrointestinal stromal tumor; Paragangliomas 3 | 2022-10-31 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 146 of the SDHC protein (p.Pro146Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SDHC-related conditions. ClinVar contains an entry for this variant (Variation ID: 142904). 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. 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. |
| St. |
RCV002254682 | SCV002525987 | uncertain significance | Paragangliomas 3 | 2022-01-06 | criteria provided, single submitter | clinical testing | The SDHC c.436C>A (p.Pro146Thr) missense change is absent in gnomAD v2.1.1 (PM2_supporting; https://gnomad.broadinstitute.org/). Five of seven in silico tools predict a benign effect of this variant on protein function (BP4), but these predictions have not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with hereditary paraganglioma-pheochromocytoma. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_Supporting, BP4 |
| Fulgent Genetics, |
RCV002483272 | SCV002783358 | uncertain significance | Gastrointestinal stromal tumor; Carney-Stratakis syndrome; Paragangliomas 3 | 2022-03-06 | criteria provided, single submitter | clinical testing | |
| Baylor Genetics | RCV003474790 | SCV004203063 | uncertain significance | Gastrointestinal stromal tumor | 2023-09-06 | criteria provided, single submitter | clinical testing | |
| Prevention |
RCV004751282 | SCV005361111 | uncertain significance | SDHC-related disorder | 2024-05-16 | no assertion criteria provided | clinical testing | The SDHC c.436C>A variant is predicted to result in the amino acid substitution p.Pro146Thr. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare, and is reported as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/142904/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |