Total submissions: 9
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000492504 | SCV000581221 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2022-09-06 | criteria provided, single submitter | clinical testing | The p.R50C variant (also known as c.148C>T), located in coding exon 3 of the SDHC gene, results from a C to T substitution at nucleotide position 148. The arginine at codon 50 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been detected in multiple individuals with personal or family history of pheochromocytoma and/or paraganglioma (Neumann HP et al. Cancer Res. 2009 Apr 15;69:3650-6; Rattenberry E et al. J. Clin. Endocrinol. Metab. 2013 Jul;98:E1248-56; McInerney-Leo AM et al. Clin. Endocrinol. (Oxf) 2014 Jan;80:25-33; Bennedbaek M et al. Hered. Cancer Clin. Pract. 2016 Jun;14:13; Andrews KA et al. J. Med. Genet., 2018 Jun;55:384-394; Casey RT et al. Sci Rep, 2019 07;9:10244; Main AM et al. Endocr Connect, 2020 Aug;9:793-803). Additionally, this alteration was identified in a minor diagnosed with acute promyelocytic leukemia (Byrjalsen A et al. PLoS Genet, 2020 12;16:e1009231). In a yeast-based functional study, this alteration resulted in a significant reduction of SDH enzyme activity (Panizza E et al. Hum. Mol. Genet. 2013 Feb;22:804-15). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Invitae | RCV000641913 | SCV000763563 | pathogenic | Gastrointestinal stromal tumor; Paragangliomas 3 | 2023-12-30 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 50 of the SDHC protein (p.Arg50Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with pheochromocytoma or head and neck paranglioma (PMID: 19351833, 23666964, 24102379). ClinVar contains an entry for this variant (Variation ID: 135194). 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 SDHC protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SDHC function (PMID: 23175444). For these reasons, this variant has been classified as Pathogenic. |
| ARUP Laboratories, |
RCV000756631 | SCV000884502 | uncertain significance | not provided | 2020-11-30 | criteria provided, single submitter | clinical testing | The SDHC c.148C>T; p.Arg50Cys variant (rs587778661) is reported in the literature in individuals affected with head and neck paraganglioma (Bennedbaek 2016, McInerney-Leo 2014, Neumann 2009, Rattenberry 2013). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 50 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.976). Additionally, a functional study of the orthologous variant in yeast suggests a mild effect on activity (Panizza 2013); however, it is unclear if this mild effect is clinically significant. Due to limited information, the clinical significance of the p.Arg50Cys variant is uncertain at this time. References: Bennedbaek M et al. Identification of eight novel SDHB, SDHC, SDHD germline variants in Danish pheochromocytoma/paraganglioma patients. Hered Cancer Clin Pract. 2016 Jun 8;14:13. McInerney-Leo AM et al. Whole exome sequencing is an efficient and sensitive method for detection of germline mutations in patients with phaeochromcytomas and paragangliomas. Clin Endocrinol (Oxf). 2014 Jan;80(1):25-33. Neumann HP et al. Clinical predictors for germline mutations in head and neck paraganglioma patients: cost reduction strategy in genetic diagnostic process as fall-out. Cancer Res. 2009 Apr 15;69(8):3650-6. Panizza E et al. Yeast model for evaluating the pathogenic significance of SDHB, SDHC and SDHD mutations in PHEO-PGL syndrome. Hum Mol Genet. 2013 Feb 15;22(4):804-15. Rattenberry E et al. A comprehensive next generation sequencing-based genetic testing strategy to improve diagnosis of inherited pheochromocytoma and paraganglioma. J Clin Endocrinol Metab. 2013 Jul;98(7):E1248-56. |
| Laboratory for Molecular Medicine, |
RCV000826184 | SCV000967727 | likely pathogenic | Hereditary pheochromocytoma-paraganglioma | 2018-02-09 | criteria provided, single submitter | clinical testing | The p.Arg50Cys variant in SDHC has been reported in 4 individuals with hereditar y paraganglioma-pheochromocytoma syndrome (Neuman 2009, Rattenberry 2013, McIner ney-Leo 2014, Bennedbaek 2016), and segregated with the disease in 1 affected re lative (Bennedbaek 2016). It has also been reported by other clinical laboratori es in ClinVar (Variation ID 135194). The variant was absent from large populatio n studies, though it was identified in a reportedly healthy individual (<50yrs; Bodian 2014). In vitro functional studies provide some evidence that the p.Arg50 Cys variant may impact protein function in yeast (Panizza 2013) and computationa l prediction tools and conservation analysis suggest that the p.Arg50Cys variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg50Cys variant is likely pat hogenic. ACMG/AMP Criteria applied (Richards 2015): PM2; PS4_Moderate; PP3; PS3_ Supporting. |
| Gene |
RCV000756631 | SCV001983844 | likely pathogenic | not provided | 2023-10-25 | criteria provided, single submitter | clinical testing | Published functional studies in yeast demonstrate reduced SDH enzyme activity (PMID: 23175444); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23666964, 19351833, 24728327, 27279923, 25394176, 22517557, 31308404, 29386252, 20236688, 24102379, 33332384, 31567591, 31447099, 34558728, 32688340, 37019617, 23175444, 26273102) |
| Center for Genomic Medicine, |
RCV000756631 | SCV002552551 | likely pathogenic | not provided | 2023-08-15 | criteria provided, single submitter | clinical testing | |
| Baylor Genetics | RCV003474732 | SCV004203069 | likely pathogenic | Gastrointestinal stromal tumor | 2023-08-02 | criteria provided, single submitter | clinical testing | |
| Color Diagnostics, |
RCV003507252 | SCV004362293 | likely pathogenic | Paragangliomas 3 | 2023-05-17 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with cysteine at codon 50 of the SDHC protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies in yeast have shown that this variant displays reduced succincate dehydrogenase activity and increased mtDNA mutability (PMID: 23175444). This variant has been reported in numerous individuals affected with paraganglioma and/pr pheochromocytoma (PMID: 19351833, 23666964, 24102379, 27279923, 29386252, 31308404, 32688340). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. |
| ITMI | RCV000122003 | SCV000086214 | not provided | not specified | 2013-09-19 | no assertion provided | reference population |