ClinVar Miner

Submissions for variant NM_003001.5(SDHC):c.436C>A (p.Pro146Thr)

gnomAD frequency: 0.00001  dbSNP: rs541660851
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132372 SCV000187462 uncertain significance Hereditary cancer-predisposing syndrome 2022-12-29 criteria provided, single submitter clinical testing The p.P146T variant (also known as c.436C>A), located in coding exon 6 of the SDHC gene, results from a C to A substitution at nucleotide position 436. The proline at codon 146 is replaced by threonine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000534423 SCV000641443 uncertain significance Gastrointestinal stromal tumor; Paragangliomas 3 2022-10-31 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 146 of the SDHC protein (p.Pro146Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SDHC-related conditions. ClinVar contains an entry for this variant (Variation ID: 142904). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV002254682 SCV002525987 uncertain significance Paragangliomas 3 2022-01-06 criteria provided, single submitter clinical testing The SDHC c.436C>A (p.Pro146Thr) missense change is absent in gnomAD v2.1.1 (PM2_supporting; https://gnomad.broadinstitute.org/). Five of seven in silico tools predict a benign effect of this variant on protein function (BP4), but these predictions have not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with hereditary paraganglioma-pheochromocytoma. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_Supporting, BP4
Fulgent Genetics, Fulgent Genetics RCV002483272 SCV002783358 uncertain significance Gastrointestinal stromal tumor; Carney-Stratakis syndrome; Paragangliomas 3 2022-03-06 criteria provided, single submitter clinical testing
Baylor Genetics RCV003474790 SCV004203063 uncertain significance Gastrointestinal stromal tumor 2023-09-06 criteria provided, single submitter clinical testing

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