ClinVar Miner

Submissions for variant NM_003000.3(SDHB):c.317A>G (p.Asn106Ser)

gnomAD frequency: 0.00006  dbSNP: rs934514080
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000460715 SCV000553996 uncertain significance Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2025-01-22 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 106 of the SDHB protein (p.Asn106Ser). 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 breast cancer and/or paraganglioma-pheochromocytoma syndrome (PMID: 31780696, 34906457). ClinVar contains an entry for this variant (Variation ID: 412463). 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 not expected to disrupt SDHB protein function with a negative predictive value of 80%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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 RCV000563084 SCV000675061 uncertain significance Hereditary cancer-predisposing syndrome 2024-05-29 criteria provided, single submitter clinical testing The p.N106S variant (also known as c.317A>G), located in coding exon 4 of the SDHB gene, results from an A to G substitution at nucleotide position 317. The asparagine at codon 106 is replaced by serine, an amino acid with highly similar properties. This alteration was identified in an individual diagnosed with breast cancer (Dutil J et al. Sci Rep, 2019 11;9:17769). This amino acid position is well 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.
GeneDx RCV001551990 SCV001772601 uncertain significance not provided 2023-12-06 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in individuals with breast cancer, pheochromocytoma and/or paraganglioma (PMID: 31780696, 34906457); This variant is associated with the following publications: (PMID: 34906457, 31780696)
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV002465668 SCV002760623 uncertain significance not specified 2025-03-04 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV004001996 SCV004829431 uncertain significance Hereditary pheochromocytoma-paraganglioma 2024-09-23 criteria provided, single submitter clinical testing This missense variant replaces asparagine with serine at codon 106 of the SDHB protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with SDHB-related disorders in the literature. This variant has been identified in 1/31396 chromosomes 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.
Baylor Genetics RCV004568125 SCV005056645 uncertain significance Gastrointestinal stromal tumor 2023-12-20 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV005010380 SCV005631522 uncertain significance Gastrointestinal stromal tumor; Carney-Stratakis syndrome; Paragangliomas 4; Mitochondrial complex 2 deficiency, nuclear type 4 2024-01-29 criteria provided, single submitter clinical testing

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