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

dbSNP: rs747518441

Total submissions: 2

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.
All of Us Research Program, National Institutes of Health	RCV004803599	SCV005424053	likely pathogenic	Hereditary pheochromocytoma-paraganglioma	2024-06-09	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with leucine at codon 217 of the SDHB protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study in yeast has reported this variant was unable to support respiratory growth, was deficient for succinate dehydrogenase activity and displayed increased mtDNA mutability (PMID: 23175444). This variant has been reported in individuals affected with pheochromocytomas or paragangliomas (PMID: 25791839, 27867439, 29386252). This variant has been identified in 1/250910 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.