ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.529C>T (p.Arg177Cys) (rs149091125)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000470780 SCV000554003 uncertain significance Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2020-09-15 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 177 of the SDHB protein (p.Arg177Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs149091125, ExAC 0.003%). This variant has not been reported in the literature in individuals with SDHB-related disease. ClinVar contains an entry for this variant (Variation ID: 412469). 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. 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.
Ambry Genetics RCV000564144 SCV000675078 uncertain significance Hereditary cancer-predisposing syndrome 2020-07-29 criteria provided, single submitter clinical testing The p.R177C variant (also known as c.529C>T), located in coding exon 5 of the SDHB gene, results from a C to T substitution at nucleotide position 529. The arginine at codon 177 is replaced by cysteine, an amino acid with highly dissimilar properties. Alterations at the same codon, p.R177G and p.R177H, have been reported in individuals diagnosed with paraganglioma or pheochromocytoma (von Dobschuetz E et al. Endocr. Relat. Cancer, 2015 Apr;22:191-204; Fishbein L et al. Ann. Surg. Oncol., 2013 May;20:1444-50; Michałowska I et al. Neuroendocrinology, 2015 Mar;101:321-30). However, functional studies of the p.R177H variant demonstrate only a mildly impaired phenotype using a yeast model (Panizza E et al. Hum. Mol. Genet., 2013 Feb;22:804-15). This amino acid position is highly conserved in available vertebrate species. In addition, p.R177C is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000757752 SCV000886096 uncertain significance not provided 2018-02-08 criteria provided, single submitter clinical testing The SDHB c.529C>T; p.Arg177Cys variant (rs149091125), to our knowledge, is not reported in the medical literature, but it is classified as a variant of uncertain significance in ClinVar (Variant ID: 412469). This variant is also found in the non-Finnish European population with an allele frequency of 0.0036% (4/111,654 alleles) in the Genome Aggregation Database. The arginine at codon 177 is highly conserved considering 14 species up to baker’s yeast (Alamut software v2.10.0), and computational analyses predict that this variant affects the structure/function of the SDHB protein (SIFT: damaging, PolyPhen2: probably damaging). Based on the available information, the clinical significance of the p.Arg177Cys variant is uncertain at this time.
GeneDx RCV000757752 SCV001784780 uncertain significance not provided 2020-10-14 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.

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