ClinVar Miner

Submissions for variant NM_003001.5(SDHC):c.397C>T (p.Arg133Ter) (rs764575966)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000162467 SCV000212830 pathogenic Hereditary cancer-predisposing syndrome 2018-04-11 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV000232178 SCV000287802 pathogenic Gastrointestinal stromal tumor; Paragangliomas 3 2019-12-07 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the penultimate exon of the SDHC mRNA at codon 133 (p.Arg133*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 37 amino acids of the SDHC protein. This variant is present in population databases (rs764575966, ExAC 0.01%). This variant has been reported in several individuals with paragangliomas (PGLs) (PMID: 24423348, 24758179, 24523625, 17898811), an individual with gastrointestinal stromal tumor (PMID: 23282968), and as a recurrent mutation causing PGLs in the French Canadian population (PMID: 27700540). It has also been found to segregate with clear cell renal carcinoma in a large family (PMID: 23083876). ClinVar contains an entry for this variant (Variation ID: 183753). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000315495 SCV000329512 pathogenic not provided 2018-10-25 criteria provided, single submitter clinical testing This pathogenic variant is denoted SDHC c.397C>T at the cDNA level and p.Arg133Ter (R133X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA). Even though nonsense-mediated decay is not expected to occur, it is significant since the last 37 amino acids are no longer translated and is predicted to cause loss of normal protein function through protein truncation. SDHC Arg133Ter has been observed in individuals with paraganglioma/pheochromocytoma, renal cell carcinoma, and gastrointestinal stromal tumors (GIST) (Zbuk 2007, Burnichon 2009, Ricketts 2012, Miettinen 2013, Bickmann 2014, Else 2014, Bordeau 2016) and is considered pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000315495 SCV000602179 pathogenic not provided 2017-04-24 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000315495 SCV000605081 pathogenic not provided 2017-09-13 criteria provided, single submitter clinical testing The SDHC c.397C>T, p.Arg133Ter variant (rs764575966) has been reported in multiple patients diagnosed with hereditary paraganglioma syndrome (Bickmann 2014, Zbuk 2007), renal cancer (Ricketts 2012) or gastrointestinal tumors (Miettinen 2013). It is reported as pathogenic in ClinVar (Variation ID: 183753), and observed in the general population with an allele frequency of 0.003 percent (9/274720 alleles) in the Genome Aggregation Database. The variant introduces a premature termination codon, and is predicted to result in a truncated protein or an absent transcript. Based on the above information, the variant is classified as pathogenic. REFERENCES Bickmann J et al. Phenotypic variability and risk of malignancy in SDHC-linked paragangliomas: lessons from three unrelated cases with an identical germline mutation (p.Arg133*). J Clin Endocrinol Metab. 2014; 99(3):E489-96. Miettinen M et al. Immunohistochemical loss of succinate dehydrogenase subunit A (SDHA) in gastrointestinal stromal tumors (GISTs) signals SDHA germline mutation. Am J Surg Pathol. 2013; 37(2):234-40. Ricketts C et al. Succinate dehydrogenase kidney cancer: an aggressive example of the Warburg effect in cancer. J Urol. 2012; 188(6):2063-71. Zbuk K et al. Germline mutations in PTEN and SDHC in a woman with epithelial thyroid cancer and carotid paraganglioma. Nat Clin Pract Oncol. 2007; 4(10):608-12.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000505285 SCV000711450 pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes 2020-04-01 criteria provided, single submitter clinical testing The p.Arg133X variant in SDHC is believed to be a French Canadian founder variant and been reported in >20 individuals, of mainly French Canadian and French ancestry, with paragangliomas/pheochromocytomas (PGL/PCC: Zbuk 2007, Burnichon 2009, Ricketts 2012, Lefevre 2014, Bickmann 2014, Shuch 2016, Bourdeau 2016). This variant segregated with PGL/PCC in at least 4 affected relatives from 2 families (Bourdeau 2016). In another family (Shuch 2016), the p.Arg133X variant segregated with both renal cell carcinoma (2 affected relatives) and PGL/PCC (1 affected relative). The p.Arg133X variant has also been identified in 0.009% (3/30782) of South Asian chromosomes by gnomAD (; dbSNP rs764575966). Please note that for diseases with clinical variability, reduced penetrance, or recessive inheritance, pathogenic variants may be present at a low frequency in the general population. This nonsense variant leads to a premature termination codon at position 133. This alteration occurs within the terminal 50 bases of the second to last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein that is missing ~22% of the coding region, with 37 amino acids removed. In summary, this variant meets criteria to be classified as pathogenic for hereditary paraganglioma-pheochromocytoma syndromes in an autosomal dominant manner based on its presence in multiple affected individuals, segregation studies, and low frequency in controls. ACMG/AMP criteria applied: PVS1_Strong, PS4, PM2, PP1_Moderate.
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000660260 SCV000782283 pathogenic Paragangliomas 3 2016-11-01 criteria provided, single submitter clinical testing
Section on Medical Neuroendocrinolgy,National Institutes of Health RCV000505285 SCV000599552 pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes no assertion criteria provided research

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