ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.688C>T (p.Arg230Cys) (rs138996609)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164435 SCV000215074 pathogenic Hereditary cancer-predisposing syndrome 2014-12-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Well-characterized mutation at same position,Deficient protein function in appropriate functional assay(s),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Other strong data supporting pathogenic classification
GeneDx RCV000520697 SCV000617569 pathogenic not provided 2017-10-05 criteria provided, single submitter clinical testing This pathogenic variant is denoted SDHB c.688C>T at the cDNA level, p.Arg230Cys (R230C) at theprotein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). This variant was observed in severalindividuals with pheochromocytoma or paraganglioma (Gimenez-Roqueplo 2003, Lefebvre 2012, Hermsen 2010,Janssen, Jochmanova 2017). In addition, functional assays have demonstrated this variant to result in an unstableprotein, and in the tumor of an individual harboring this variant, complete and selective loss of mitochondrial complex IIenzyme activity was observed (Yang 2012, Gimenez-Roqueplo 2003). SDHB Arg230Cys was not observed at asignificant allele frequency in large population cohorts (Lek 2016). Since Arginine and Cysteine differ in polarity,charge, size or other properties, this is considered a non-conservative amino acid substitution. SDHB Arg230Cysoccurs at a position that is conserved across species and is not located in a known functional domain. In silicoanalyses predict that this pathogenic variant is probably damaging to protein structure and function. Based on currentlyavailable evidence, we consider this variant to be pathogenic
Invitae RCV000528137 SCV000644765 pathogenic Gastrointestinal stroma tumor; Paragangliomas 4; Pheochromocytoma 2018-11-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 230 of the SDHB protein (p.Arg230Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs138996609, ExAC 0.002%). This variant has been reported in several individuals affected with malignant or non-malignant pheochromocytoma or paraganglioma (PMID: 14500403, 17652212, 25873086, 19454582, 20208144, 22517554). ClinVar contains an entry for this variant (Variation ID: 185077). Experimental studies have shown that this missense change results in reduced SDHB protein stability (PMID: 22835832). Two other missense substitutions at this codon (p.Arg230His and p.Arg230Leu) have been determined to be pathogenic (PMID: 18382370, 19351833, 23934599, Invitae). This suggests that the arginine residue is critical for SDHB protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Center for Human Genetics, Inc RCV000660258 SCV000782279 pathogenic Paragangliomas 4 2016-11-01 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000660258 SCV000840068 pathogenic Paragangliomas 4 2018-01-14 criteria provided, single submitter clinical testing The c.688C>T (p.Arg230Cys) variant in the SDHB gene has been reported in several unrelated individuals with pheochromocytoma or paraganglioma (PMID: 14500403, 24939699, 20208144, and 28374168). Functional assays have demonstrated that this missense change results in an unstable protein, and in the tumor of an individual with this variant complete and selective loss of mitochondrial complex II enzyme activity was observed (PMID: 22835832, 14500403). Additionally, two other pathogenic/likely pathogenic missense substitutions at this codon have been reported (PMID: 22835832, 23934599, 18382370, and 19351833,) suggesting that the Arg230 residue is critical for normal functioning of the SDHB protein. In light of the currently available data this variant in the SDHB gene is classified pathogenic.
Section on Medical Neuroendocrinolgy,National Institutes of Health RCV000505374 SCV000599523 pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes no assertion criteria provided research

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