ClinVar Miner

Submissions for variant NM_003000.3(SDHB):c.307A>G (p.Met103Val)

gnomAD frequency: 0.00004  dbSNP: rs140178341
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000227754 SCV000287769 uncertain significance Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2025-01-28 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 103 of the SDHB protein (p.Met103Val). This variant is present in population databases (rs140178341, gnomAD 0.1%). This missense change has been observed in individual(s) with kidney cancer and/or pheochromocytomas and paragangliomas (PMID: 34906457, 35957908). ClinVar contains an entry for this variant (Variation ID: 239429). 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 RCV000568674 SCV000664492 likely benign Hereditary cancer-predisposing syndrome 2019-12-04 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Fulgent Genetics, Fulgent Genetics RCV000763773 SCV000894675 uncertain significance Carney-Stratakis syndrome; Paragangliomas 4; Pheochromocytoma 2018-10-31 criteria provided, single submitter clinical testing
Mendelics RCV000986265 SCV001135204 uncertain significance Gastrointestinal stromal tumor 2019-05-28 criteria provided, single submitter clinical testing
Baylor Genetics RCV001294087 SCV001482893 uncertain significance Pheochromocytoma 2019-09-10 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx RCV001575148 SCV001802075 uncertain significance not provided 2024-05-30 criteria provided, single submitter clinical testing Observed in individuals with paraganglioma/pheochromocytoma, kidney cancer, or neuroectodermal tumor (PMID: 34906457, 35957908, 38093606); 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: 29684080, 32948195, 34906457, 35957908, 38093606)
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV002291606 SCV002584683 uncertain significance Paragangliomas 4 2022-09-29 criteria provided, single submitter clinical testing The SDHB c.307A>G (p.Met103Val) missense change has a maximum frequency of 0.095% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/ ). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with hereditary paraganglioma-pheochromocytoma. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Baylor Genetics RCV000986265 SCV004202979 uncertain significance Gastrointestinal stromal tumor 2024-03-22 criteria provided, single submitter clinical testing

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