Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000130852 | SCV000185750 | pathogenic | Hereditary cancer-predisposing syndrome | 2024-05-31 | criteria provided, single submitter | clinical testing | The p.C192Y pathogenic mutation (also known as c.575G>A), located in coding exon 6 of the SDHB gene, results from a G to A substitution at nucleotide position 575. The cysteine at codon 192 is replaced by tyrosine, an amino acid with highly dissimilar properties. This mutation has been reported in multiple individuals diagnosed with paraganglioma-pheochromocytoma (PGL-PCC) syndrome (Benn DE et al. J Clin Endocrinol Metab. 2006 Mar;91(3):827-36; Burnichon N et al. J Clin Endocrinol Metab. 2009 Aug;94(8):2817-27; Jochmanova I et al. J. Cancer Res. Clin. Oncol. 2017 Aug;143:1421-1435). The cysteine at codon 192 has been shown to play a vital role coordinating the iron-sulfur cluster in SDHB protein (Iverson TM et al. J Biol Chem. 2012 Oct 12;287(42):35430-8). In addition, another alteration at codon 192 (p.C192R) has been reported in two individuals, one with a sporadic pheochromocytoma and the other with a paraganglioma (Neumann HP et al. N Engl J Med. 2002 May 9;3466(19):1459-66; Burnichon N et al. J Clin Endocrinol Metab. 2009 Aug;94(8):2817-27). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. |
| Labcorp Genetics |
RCV002514739 | SCV003522745 | pathogenic | Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma | 2023-01-16 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys192 amino acid residue in SDHB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12000816, 17200167, 18382370, 22517554, 25371406, 27785149). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SDHB protein function. ClinVar contains an entry for this variant (Variation ID: 142047). This missense change has been observed in individuals with SDHB-related conditions (PMID: 16317055, 19454582, 28374168, 34906457; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 192 of the SDHB protein (p.Cys192Tyr). |
| Section on Medical Neuroendocrinolgy, |
RCV000505338 | SCV000599519 | likely pathogenic | Hereditary pheochromocytoma-paraganglioma | no assertion criteria provided | research |