ClinVar Miner

Submissions for variant NM_003001.3(SDHC):c.148C>T (p.Arg50Cys) (rs587778661)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000756631 SCV000884502 uncertain significance not provided 2017-07-05 criteria provided, single submitter clinical testing The SDHC c.148C>T;p.Arg50Cys variant has been described in the medical literature in individuals with head and neck paraganglioma (Bennedbaek 2016, Neumann 2009, Rattenberry 2013). However, the variant has also been described in a healthy population (Bodian 2014). The variant is listed in the ClinVar database (Variation ID: 135194) and the dbSNP variant database (rs587778661) but is not described in the general population-based databases (Exome Variant Server, Genome Aggregation Database). The amino acid at this position is highly conserved across species and computational algorithms (PolyPhen2, SIFT) predict this variant is deleterious. In agreement with the predictions, at least one functional study in yeast describes a mild effect on activity (Panizza 2013). However, based on available information, there is insufficient evidence to classify the variant with certainty. 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. Bodian DL et al. Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing. PLoS One. 2014 Apr 11;9(4):e94554. 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.
Ambry Genetics RCV000492504 SCV000581221 likely pathogenic Hereditary cancer-predisposing syndrome 2018-03-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
ITMI RCV000122003 SCV000086214 not provided not specified 2013-09-19 no assertion provided reference population
Invitae RCV000641913 SCV000763563 likely pathogenic Gastrointestinal stroma tumor; Paragangliomas 3 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 50 of the SDHC protein (p.Arg50Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with pheochromocytoma (PMID: 24102379), head and neck paranglioma (PMID: 19351833, 23666964) and segregated with disease in an offspring of an individual affected with paraganglioma (PMID: 27279923). ClinVar contains an entry for this variant (Variation ID: 135194). Experimental in vitro studies in a yeast model system have shown that this missense change does not affect oxidative growth but it results in a partial reduction of SDH enzyme activity (PMID: 23175444). In summary, this variant is a rare missense change that has been reported in several affected individuals and partially affects SDH protein function. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000826184 SCV000967727 likely pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes 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.

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