ClinVar Miner

Submissions for variant NM_003000.3(SDHB):c.5C>T (p.Ala2Val)

dbSNP: rs199948437
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000633973 SCV000755246 uncertain significance Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2024-09-30 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2 of the SDHB protein (p.Ala2Val). 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 variant has not been reported in the literature in individuals affected with SDHB-related conditions. ClinVar contains an entry for this variant (Variation ID: 528745). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SDHB protein function. 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV002268223 SCV002552296 uncertain significance not specified 2025-03-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV002358781 SCV002656151 uncertain significance Hereditary cancer-predisposing syndrome 2023-11-13 criteria provided, single submitter clinical testing The p.A2V variant (also known as c.5C>T), located in coding exon 1 of the SDHB gene, results from a C to T substitution at nucleotide position 5. The alanine at codon 2 is replaced by valine, an amino acid with similar properties. This alteration was detected in a 49 year old female with a prolactin pituitary adenoma, primary hyperparathyroidism, and parathyroid tumor tissue that demonstrated preserved staining for SDHA and SDHB immunohistochemistry. The family history included an aunt with Cushing's disease; however, there was no known family history of paraganglioma or pheochromocytoma (De Sousa SMC et al. Eur J Endocrinol, 2017 May;176:635-644). 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 RCV004003831 SCV004832808 uncertain significance Hereditary pheochromocytoma-paraganglioma 2023-06-26 criteria provided, single submitter clinical testing This missense variant replaces alanine with valine at codon 2 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 been reported in individuals affected with hereditary pituitary adenoma syndrome (PMID: 28220018). 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.
Baylor Genetics RCV004568393 SCV005056646 uncertain significance Gastrointestinal stromal tumor 2023-12-19 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV005000408 SCV005624031 uncertain significance not provided 2024-03-11 criteria provided, single submitter clinical testing

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