ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.566G>T (p.Cys189Phe) (rs876658540)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000215934 SCV000273922 likely pathogenic Hereditary cancer-predisposing syndrome 2015-02-17 criteria provided, single submitter clinical testing The p.C189F variant (also known as c.566G>T), located in coding exon 6 of the SDHB gene, results from a G to T substitution at nucleotide position 566. The cysteine at codon 189 is replaced by phenylalanine, an amino acid with highly dissimilar properties. <span style="background-color:initial">The Cys189 residue plays a vital role coordinating the Fe4S4 cluster and it is believed that alterations at this location would prevent assembly of Complex II<span style="background-color:initial">(Iverson TM, J. Biol. Chem. 2012 Oct; 287(42):35430-8).This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.03% (greater than 3200 alleles tested) in our clinical cohort.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 RCV001327188 SCV001518250 uncertain significance Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2020-06-28 criteria provided, single submitter clinical testing This sequence change replaces cysteine with phenylalanine at codon 189 of the SDHB protein (p.Cys189Phe). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with paraganglioma (PMID: 19001511, Invitae). ClinVar contains an entry for this variant (Variation ID: 230387). 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. This variant disrupts the p.Cys189 amino acid residue in SDHB. Other variant(s) that disrupt this residue have been observed in individuals with SDHB-related conditions (PMID: 27279923), which suggests that this may be a clinically significant amino acid residue. 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.
Section on Medical Neuroendocrinolgy,National Institutes of Health RCV000505376 SCV000599520 likely pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes no assertion criteria provided research

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