ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.634C>T (p.Leu212Phe) (rs1228560456)

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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 RCV000565195 SCV000664534 likely pathogenic Hereditary cancer-predisposing syndrome 2018-11-26 criteria provided, single submitter clinical testing The p.L212F variant (also known as c.634C>T), located in coding exon 6 of the SDHB gene, results from a C to T substitution at nucleotide position 634. The leucine at codon 212 is replaced by phenylalanine, an amino acid with highly similar properties. This variant has been identified in an individual with recurrent paragangliomas, whose tumor showed absent SDHB on immunohistochemistry (Internal Ambry data). Based on internal structural analysis, the leucine is located near the sulfur-binding center of the SDHB protein, and this variant is anticipated to disrupt its folding (Sun F et al. Cell. 2005 Jul;121:1043-57). This variant was not reported in the gnomAD database, with coverage at this position. 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 RCV000697509 SCV000826124 uncertain significance Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2018-03-16 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 212 of the SDHB protein (p.Leu212Phe). 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. ClinVar contains an entry for this variant (Variation ID: 480792). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; 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.

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