Submissions for variant NM_003000.3(SDHB):c.326A>G (p.Asn109Ser)

dbSNP: rs1570948643

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000820137	SCV000960833	uncertain significance	Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma	2024-11-18	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 109 of the SDHB protein (p.Asn109Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of SDHB-related conditions (PMID: 34906457). ClinVar contains an entry for this variant (Variation ID: 662485). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SDHB protein function with a positive predictive value of 80%. 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	RCV002442749	SCV002612398	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-03	criteria provided, single submitter	clinical testing	The p.N109S variant (also known as c.326A>G), located in coding exon 4 of the SDHB gene, results from an A to G substitution at nucleotide position 326. The asparagine at codon 109 is replaced by serine, an amino acid with highly similar properties. This alteration has been reported in a paraganglioma and/or pheochromocytoma patient (Garrett A et al. Genet Med, 2022 Jan;24:41-50). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV004803266	SCV005424067	uncertain significance	Hereditary pheochromocytoma-paraganglioma	2024-03-24	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 109 of the SDHB protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with paraganglioma and/or pheochromocytoma in the literature (PMID: 34906457). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.