ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.289A>T (p.Ile97Phe) (rs1553177769)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000567029 SCV000664500 likely pathogenic Hereditary cancer-predisposing syndrome 2020-03-20 criteria provided, single submitter clinical testing The p.I97F variant (also known as c.289A>T), located in coding exon 4 of the SDHB gene, results from an A to T substitution at nucleotide position 289. The isoleucine at codon 97 is replaced by phenylalanine, an amino acid with highly similar properties. This variant has been detected in multiple unrelated individuals with paraganglioma (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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 RCV000693661 SCV000821539 likely pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2019-12-25 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with phenylalanine at codon 97 of the SDHB protein (p.Ile97Phe). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with paraganglioma or pheochromocytoma (Invitae, external communication). ClinVar contains an entry for this variant (Variation ID: 480784). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C1). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 5

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