ClinVar Miner

Submissions for variant NM_003001.5(SDHC):c.43C>T (p.Arg15Ter) (rs201286421)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000128874 SCV000172731 pathogenic Hereditary cancer-predisposing syndrome 2018-09-28 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV000627763 SCV000287805 pathogenic Gastrointestinal stromal tumor; Paragangliomas 3 2019-11-12 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg15*) in the SDHC gene. It is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in the literature in multiple individuals affected with paraganglioma, Hodgkin's lymphoma, pheochromocytoma, and/or gastrointestinal stromal tumors (PMID: 17667967, 21106325, 22868853, 24781345, 19351833). ClinVar contains an entry for this variant (Variation ID: 41776). Loss-of-function variants in SDHC are known to be pathogenic (PMID: 19454582, 24758179). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000486068 SCV000565546 pathogenic not provided 2018-04-23 criteria provided, single submitter clinical testing This variant is denoted SDHC c.43C>T at the cDNA level and p.Arg15Ter (R15X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported multiple times in association with hereditary paraganglioma/pheochromocytoma (PGL/PCC) syndrome (Pasini 2008, Vandy 2011, Illouz 2012, Renella 2014, Bennedbaek 2016). We consider this variant to be pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000505325 SCV000731535 pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes 2017-03-01 criteria provided, single submitter clinical testing The p.Arg15X variant in SDHC has been reported in at least 6 individuals with SD HC-associated cancers (Pasini 2008, Vandy 2011, Illouz 2012, Renella 2014, Else 2014). This variant has been identified in 1/16446 South Asian chromosomes by th e Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs20 1286421). This nonsense variant leads to a premature termination codon at positi on 15, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the SDHC gene is an established disease mechanism in indivi duals with hereditary paragangliomas and pheochromocytomas. In summary, this var iant meets criteria to be classified as pathogenic for hereditary paragangliomas and pheochromocytomas in an autosomal dominant manner.
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000034695 SCV000782282 pathogenic Paragangliomas 3 2016-11-01 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034695 SCV000043489 pathogenic Paragangliomas 3 2012-07-13 no assertion criteria provided research Converted during submission to Pathogenic.
Section on Medical Neuroendocrinolgy,National Institutes of Health RCV000505325 SCV000599553 pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes no assertion criteria provided research

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