Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001064015 | SCV001228888 | uncertain significance | Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma | 2023-12-29 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 127 of the SDHB protein (p.Ile127Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with paraganglioma (PMID: 31492822). ClinVar contains an entry for this variant (Variation ID: 858190). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SDHB protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect SDHB function (PMID: 23175444). This variant disrupts the p.Ile127 amino acid residue in SDHB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15987702, 16916404, 19802898, 21820839, 25972245). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 | RCV003353144 | SCV004053359 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-06-29 | criteria provided, single submitter | clinical testing | The p.I127V variant (also known as c.379A>G), located in coding exon 4 of the SDHB gene, results from an A to G substitution at nucleotide position 379. The isoleucine at codon 127 is replaced by valine, an amino acid with highly similar properties. In one yeast-based functional study, this alteration demonstrated function similar to wildtype (Panizza E et al. Hum Mol Genet, 2013 Feb;22:804-15). This alteration has been reported in an individual with pheochromocytoma and/or paraganglioma (Bayley JP et al. J Med Genet, 2020 Feb;57:96-103). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |