ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.724C>A (p.Arg242Ser) (rs786203251)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492633 SCV000581213 pathogenic Hereditary cancer-predisposing syndrome 2017-07-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),Well-characterized mutation at same position,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
GeneDx RCV000523546 SCV000616875 pathogenic not provided 2017-05-25 criteria provided, single submitter clinical testing This pathogenic variant is denoted SDHB c.724C>A at the cDNA level, p.Arg242Ser (R242S) at theprotein level, and results in the change of an Arginine to a Serine (CGC>AGC). This variant has been reported in atleast two individuals with head and neck paraganglioma (Neumann 2009). Functional assays in yeast demonstratedthat this variant affects SDH enzyme activity and increases mtDNA mutability and sensitivity to oxidative stress(Panizza 2013). SDHB Arg242Ser was not observed in large population cohorts (NHLBI Exome Sequencing Project,The 1000 Genomes Consortium 2015, Lek 2016). Since Arginine and Serine differ in some properties, this isconsidered a semi-conservative amino acid substitution. SDHB Arg242Ser occurs at a position that is conservedacross species and is located in the second L(I)YR motif (Maio 2014, Saxena 2015). In silico analyses predict that thispathogenic variant is probably damaging to protein structure and function. Based on currently available evidence, weconsider this variant to be pathogenic
Invitae RCV000226466 SCV000287789 likely pathogenic Gastrointestinal stroma tumor; Paragangliomas 4; Pheochromocytoma 2018-05-12 criteria provided, single submitter clinical testing This sequence change replaces arginine with serine at codon 242 of the SDHB protein (p.Arg242Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in 2 individuals affected with head and neck paraganglioma (PMID: 19351833) and an individual with malignant paraganglioma in the Invitae database. ClinVar contains an entry for this variant (Variation ID: 239443). An experimental study has shown that this missense change disrupts protein function, resulting in increased mitochondrial DNA mutability and sensitivity to oxidative stress in a yeast model system (PMID: 23175444). Two different missense substitutions at this codon (p.Arg242His and p.Arg242Cys) have been determined to be pathogenic (PMID: 19351833, 21173220, 22517554). This suggests that the arginine residue is critical for SDHB protein function and that other missense substitutions at this position may also be pathogenic. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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