Total submissions: 17
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000492504 | SCV000581221 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2024-09-25 | 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 a personal and/or family history that is consistent with SDHC-related disease (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; Sen I et al. J Vasc Surg, 2020 May;71:1602-1612.e2; Williams ST et al. Clin Endocrinol (Oxf), 2022 Apr;96:499-512). 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. |
| Labcorp Genetics |
RCV000641913 | SCV000763563 | pathogenic | Gastrointestinal stromal tumor; Paragangliomas 3 | 2025-01-30 | 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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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 | likely pathogenic | not provided | 2024-12-31 | criteria provided, single submitter | clinical testing | The SDHC c.148C>T; p.Arg50Cys variant (rs587778661, ClinVar Variation ID: 135194) is reported in the literature in multiple individuals affected with head and neck paraganglioma (Andrews 2018, Bennedbaek 2016, Haverfield 2021, Main 2020, McInerney-Leo 2014, Neumann 2009, Rattenberry 2013, Sen 2020, Williams 2022). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Functional analyses of the variant protein in yeast showed a reduction in enzyme activity (Panizza 2013). Computational analyses predict that this variant is deleterious (REVEL: 0.976). Based on available information, this variant is considered to be likely pathogenic. References: Andrews KA et al. Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD. J Med Genet. 2018 Jun. PMID: 29386252 Bennedbaek M et al. Identification of eight novel SDHB, SDHC, SDHD germline variants in Danish pheochromocytoma/paraganglioma patients. Hered Cancer Clin Pract. 2016 PMID: 27279923 Haverfield EV et al. Physician-directed genetic screening to evaluate personal risk for medically actionable disorders: a large multi-center cohort study. BMC Med. 2021 Aug 18. PMID: 34404389 Main AM et al. Genotype-phenotype associations in PPGLs in 59 patients with variants in SDHX genes. Endocr Connect. 2020 Aug. PMID: 32688340 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. PMID: 24102379 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. PMID: 19351833 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. PMID: 23175444 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. PMID: 23666964 Sen I et al. Tumor-specific prognosis of mutation-positive patients with head and neck paragangliomas. J Vasc Surg. 2020 May. PMID: 32035780 Williams ST et al. SDHC phaeochromocytoma and paraganglioma: A UK-wide case series. Clin Endocrinol (Oxf). 2022 Apr. PMID: 34558728 |
| 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 | 2024-12-04 | 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, 26273102, 32035780, 30201732, 23175444) |
| Center for Genomic Medicine, |
RCV000756631 | SCV002552551 | likely pathogenic | not provided | 2025-03-04 | criteria provided, single submitter | clinical testing | |
| Baylor Genetics | RCV003474732 | SCV004203069 | likely pathogenic | Gastrointestinal stromal tumor | 2024-02-07 | 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. |
| All of Us Research Program, |
RCV000826184 | SCV004821958 | likely pathogenic | Hereditary pheochromocytoma-paraganglioma | 2024-09-18 | 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. |
| Myriad Genetics, |
RCV003507252 | SCV004933615 | likely pathogenic | Paragangliomas 3 | 2024-02-08 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 31308404, 27279923, 30201732]. This variant is expected to disrupt protein structure [Myriad internal data]. |
| Human Genome Sequencing Center Clinical Lab, |
RCV003507252 | SCV005045794 | likely pathogenic | Paragangliomas 3 | 2023-09-05 | criteria provided, single submitter | clinical testing | This c.148C>T (p.Arg50Cys) variant in the SDHC gene has been reported in multiple unrelated patients with pheochromocytoma or paraganglioma (PMID: 19351833, 23666964, 24102379, 24728327, 27279923, 29386252, 31308404, 32688340) and segregated with the disease (PMID: 27279923). In addition, this variant was also identified in individuals with acute promyelocytic leukemia (PMID: 33332384). This variant is absent in the general population database. In vitro studies in the yeast showed that this variant significantly decreased succinate dehydrogenase activity (PMID: 23175444). Therefore, this c.148C>T (p.Arg50Cys) variant in the SDHC gene is classified as likely pathogenic. |
| Ce |
RCV000756631 | SCV005051187 | likely pathogenic | not provided | 2024-05-01 | criteria provided, single submitter | clinical testing | SDHC: PM2, PS3:Moderate, PS4:Moderate |
| Clinical Genetics Laboratory, |
RCV000756631 | SCV005198197 | likely pathogenic | not provided | 2023-08-23 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000826184 | SCV005203412 | pathogenic | Hereditary pheochromocytoma-paraganglioma | 2024-07-18 | criteria provided, single submitter | clinical testing | Variant summary: SDHC c.148C>T (p.Arg50Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251468 control chromosomes. c.148C>T has been reported in the literature in multiple individuals affected with Hereditary Paraganglioma-Pheochromocytoma Syndrome (Benn_2018, Bennedbaek_2016, Mclnerney-Leo_2014, Neumann_2009, Rattenberry_2013). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The variant was shown to affect protein function (Panizza_2012). The following publications have been ascertained in the context of this evaluation (PMID: 30201732, 27279923, 24102379, 19351833, 23175444, 23666964). ClinVar contains an entry for this variant (Variation ID: 135194). Based on the evidence outlined above, the variant was classified as pathogenic. |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000756631 | SCV005624042 | likely pathogenic | not provided | 2024-05-20 | criteria provided, single submitter | clinical testing | The SDHC c.148C>T (p.Arg50Cys) variant has been reported in the published literature in individuals affected with hereditary paraganglioma/pheochromocytoma syndrome (PMID: 34558728 (2022), 32688340 (2020), 32035780 (2020), 29386252 (2018), 27279923 (2016), 24102379 (2014), 23666964 (2013), 19351833 (2009)). Additionally, a functional study performed in a yeast model did not conclusively demonstrate a damaging effect of the orthologous variant on protein function (PMID: 23175444 (2013)). The frequency of this variant in the general population, 0.0000066 (1/152142 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic. |
| Department of Clinical Genetics, |
RCV000826184 | SCV005689552 | likely pathogenic | Hereditary pheochromocytoma-paraganglioma | 2025-01-24 | criteria provided, single submitter | clinical testing | The following ACMG criteria have been used in classification: PM2_SUP (gnomAD 3.1.2, non-cancer); PP3; PS4_MOD; PS3_SUP; PP1. Observed in several healthy individuals, which may indicate reduced penetrance |
| ITMI | RCV000122003 | SCV000086214 | not provided | not specified | 2013-09-19 | no assertion provided | reference population |