ClinVar Miner

Submissions for variant NM_003000.3(SDHB):c.650G>T (p.Arg217Leu)

dbSNP: rs747518441
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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001242943 SCV001416068 likely pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2023-12-27 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 217 of the SDHB protein (p.Arg217Leu). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with personal or family history of paraganglioma-pheochromocytoma syndromes (PMID: 19351833, 27867439, 29386252). ClinVar contains an entry for this variant (Variation ID: 967921). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SDHB protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SDHB function (PMID: 23175444). This variant disrupts the p.Arg217 amino acid residue in SDHB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18753105, 19351833, 19454582, 19802898, 23735539, 24659481). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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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