ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.547C>T (p.Leu183Phe) (rs1557740003)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000703565 SCV000832469 uncertain significance Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2018-05-29 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 183 of the SDHB protein (p.Leu183Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SDHB-related disease. 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 C15"). 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 Clinical Genomics Lab, St. Jude Children's Research Hospital RCV001543112 SCV001761622 uncertain significance Hereditary Paraganglioma-Pheochromocytoma Syndromes 2021-06-24 criteria provided, single submitter clinical testing The SDHB c.547C>T (p.Leu183Phe) missense change is absent in gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org/). Seven of seven in silico tools predict a deleterious effect of this variant on protein function (PP3), but to our knowledge these predictions have not been confirmed by functional assays. 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, PP3.

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