ClinVar Miner

Submissions for variant NM_003001.5(SDHC):c.148C>T (p.Arg50Cys)

gnomAD frequency: 0.00001  dbSNP: rs587778661
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492504 SCV000581221 likely pathogenic Hereditary cancer-predisposing syndrome 2024-01-22 criteria provided, single submitter clinical testing The c.148C>T (p.R50C) alteration is located in coding exon 3 of the SDHC gene. This alteration results from a C to T substitution at nucleotide position 148, causing the arginine (R) at amino acid position 50 to be replaced by a cysteine (C). Based on data from gnomAD, the T allele has an overall frequency of 0.001% (1/152142) total alleles studied. The highest observed frequency was 0.001% (1/68030) of European (non-Finnish) alleles. This alteration has been detected in multiple individuals with a personal and/or family history that is consistent with SDHC-related disease (Neumann, 2009; Rattenberry, 2013; McInerney-Leo, 2014; Bennedbæk, 2016; Andrews, 2018; Casey, 2019; Main, 2020; Sen, 2020; Williams, 2022). Additionally, this alteration was identified in a minor diagnosed with acute promyelocytic leukemia (Byrjalsen, 2020). This amino acid position is highly conserved in available vertebrate species. In a yeast-based functional study, this alteration resulted in a significant reduction of SDH enzyme activity (Panizza, 2013). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely 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, Molecular Genetics and Genomics, 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, Mass General Brigham Personalized 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.
GeneDx 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, Rigshospitalet, Copenhagen University Hospital RCV000756631 SCV002552551 likely pathogenic not provided 2023-08-15 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, LLC DBA Color Health 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, National Institutes of Health RCV000826184 SCV004821958 likely pathogenic Hereditary pheochromocytoma-paraganglioma 2024-01-05 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, Inc. 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, Baylor College of Medicine 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.
CeGaT Center for Human Genetics Tuebingen RCV000756631 SCV005051187 likely pathogenic not provided 2024-05-01 criteria provided, single submitter clinical testing SDHC: PM2, PS3:Moderate, PS4:Moderate
ITMI RCV000122003 SCV000086214 not provided not specified 2013-09-19 no assertion provided reference population

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