Submissions for variant NM_003000.3(SDHB):c.49A>G (p.Thr17Ala)

gnomAD frequency: 0.00001  dbSNP: rs1060503756

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000468636	SCV000553994	uncertain significance	Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 17 of the SDHB protein (p.Thr17Ala). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with paraganglioma and/or pheochromocytoma (PMID: 22293219, 26269449, 29386252, 30050099). ClinVar contains an entry for this variant (Variation ID: 412461). 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 not expected to disrupt SDHB protein function with a negative predictive value of 95%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV001023387	SCV001185255	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-12	criteria provided, single submitter	clinical testing	The p.T17A variant (also known as c.49A>G), located in coding exon 1 of the SDHB gene, results from an A to G substitution at nucleotide position 49. The threonine at codon 17 is replaced by alanine, an amino acid with similar properties. This alteration has been identified in multiple individuals with paragangliomas and/or pheochromocytomas (Domingues R et al. J. Endocrinol. Invest. 2012 Dec;35:975-80; Cascón A et al. Endocr Relat Cancer, 2013 Jun;20:L1-6; Donato S et al. Endocrine, 2019 08;65:408-415; Richter S et al. Genet. Med., 2019 03;21:705-717). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. This amino acid position is poorly conserved in available vertebrate species and alanine is the reference amino acid in many other vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003114593	SCV003800924	uncertain significance	not specified	2023-01-19	criteria provided, single submitter	clinical testing	Variant summary: SDHB c.49A>G (p.Thr17Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 242948 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.49A>G has been reported in the literature as a VUS/likely benign variant in individuals affected with features of single pheochromocytoma and/or paraganglioma (example, PMID: 22293219, 30050099, 23404858, 31104306, 29386252, 26269449). These report(s) do not provide unequivocal conclusions about association of the variant with Pheochromocytoma. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV003221995	SCV003918745	uncertain significance	not provided	2023-04-11	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal or family history of paraganglioma, but tumor studies in one individual implicated VHL as the causative locus and also did not find an elevated succinate: fumarate ratio (Domingues et al., 2012; Cascon et al., 2013; Andrews et al., 2018; Richter et al., 2019); This variant is associated with the following publications: (PMID: 29386252, 26269449, 26273102, 30050099, 23404858, 22293219, 31104306)