ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.221A>C (p.Asp74Ala) (rs876658713)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000222241 SCV000274333 likely pathogenic Hereditary cancer-predisposing syndrome 2020-07-28 criteria provided, single submitter clinical testing The p.D74A variant (also known as c.221A>C), located in coding exon 3 of the SDHB gene, results from an A to C substitution at nucleotide position 221. The aspartic acid at codon 74 is replaced by alanine, an amino acid with dissimilar properties. This variant was detected in multiple individuals with paraganglioma and co-segregated with disease in one family (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV000475368 SCV000554041 pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2020-10-30 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with alanine at codon 74 of the SDHB protein (p.Asp74Ala). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with paraganglioma (PGL) in a family, and has been observed in multiple individuals with PGL, gastrointestinal stromal tumor, and renal cell carcinoma including SDH-deficient tumors (Invitae, external communications). ClinVar contains an entry for this variant (Variation ID: 230694). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000507551 SCV000605079 uncertain significance not specified 2017-01-20 criteria provided, single submitter clinical testing
GeneDx RCV001551663 SCV001772221 pathogenic not provided 2019-08-19 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32741965)

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