ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.530G>A (p.Arg177His) (rs150437793)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000229109 SCV000287778 uncertain significance Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2020-10-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 177 of the SDHB protein (p.Arg177His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs150437793, ExAC 0.01%). This variant has been reported in a large family where it segregated with paragangliomas (PGL) or pheochromocytomas (PCC) in the family members (PMID: 25595276). Additionally, this variant has been reported in individuals with head and neck paragangliomas (PMID: 27867439). ClinVar contains an entry for this variant (Variation ID: 239433). Experimental studies in a yeast model system showed this variant had a mild effect on SDHB function (PMID: 23175444). 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 RCV000567446 SCV000675079 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-02 criteria provided, single submitter clinical testing The p.R177H variant (also known as c.530G>A), located in coding exon 5 of the SDHB gene, results from a G to A substitution at nucleotide position 530. The arginine at codon 177 is replaced by histidine, an amino acid with highly similar properties. This variant has been reported in multiple individuals diagnosed with paraganglioma or pheochromocytoma, and segregated with disease in one family (von Dobschuetz E et al. Endocr. Relat. Cancer, 2015 Apr;22:191-204; Michałowska I et al. Neuroendocrinology, 2015 Mar;101:321-30). However, functional studies of this 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, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited and conflicting at this time, the clinical significance of this alteration remains unclear.

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