Submissions for variant NM_003000.3(SDHB):c.137G>T (p.Arg46Leu)

dbSNP: rs772551056

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000473045	SCV000554015	pathogenic	Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma	2024-08-07	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 46 of the SDHB protein (p.Arg46Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with pheochromocytoma and paraganglioma (PHEO-PGL) syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 412478). 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.Arg46 amino acid residue in SDHB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14500403, 15328326, 25972245). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000571526	SCV000664561	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-06-02	criteria provided, single submitter	clinical testing	The p.R46L variant (also known as c.137G>T), located in coding exon 2 of the SDHB gene, results from a G to T substitution at nucleotide position 137. The arginine at codon 46 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been observed in at least one individual with a personal and/or family history that is consistent with SDHB-related disease (Ambry internal data). This alteration has been reported in a paraganglioma-pheochromocytoma cohort, and authors characterized this alteration as having severely impaired function based on reduced oxidative growth, SDH activity and respiration, as well as increased mtDNA mutability following oxidative stress (Panizza E et al. Hum. Mol. Genet., 2013 Feb;22:804-15). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Myriad Genetics, Inc.	RCV003449160	SCV004185978	likely pathogenic	Paragangliomas 4	2023-10-24	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 34906457, 37529773, 31492822, 28374168]. This variant is expected to disrupt protein structure [Myriad internal data].
GeneDx	RCV004701513	SCV005202014	likely pathogenic	not provided	2024-01-04	criteria provided, single submitter	clinical testing	Observed in individuals with a personal and/or family history of PGL/PCC referred for genetic testing at GeneDx and in published literature (PMID: 31492822, 34906457, 37529773); Functional assays in yeast demonstrated that this variant affects SDH enzyme activity (PMID: 23175444); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28374168, 31492822, 34906457, 37529773, 23175444)