Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001226209 | SCV001398513 | uncertain significance | Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma | 2023-08-03 | criteria provided, single submitter | clinical testing | 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. 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. ClinVar contains an entry for this variant (Variation ID: 953855). This missense change has been observed in individual(s) with bilateral carotid body paragangliomas (PMID: 22109755). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 111 of the SDHB protein (p.Leu111Val). |
| Ambry Genetics | RCV002451532 | SCV002611627 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2020-11-19 | criteria provided, single submitter | clinical testing | The p.L111V variant (also known as c.331C>G), located in coding exon 4 of the SDHB gene, results from a C to G substitution at nucleotide position 331. The leucine at codon 111 is replaced by valine, an amino acid with highly similar properties. This alteration was identified in a 35-year-old woman with bilateral carotid body paragangliomas who had a family history of neck masses (Peck BW et al. Laryngoscope, 2011 Dec;121:2572-5). Based on internal structural analysis, L111V disrupts the Fe2S2 binding pocket, which is sensitive to alteration (Zhou Q et al. Protein Cell, 2011 Jul;2:531-42; Inaoka DK et al. Int J Mol Sci, 2015 Jul;16:15287-308), as disruptions of the surrounding structure can change the electronic properties of the protein (Lima J et al. J Clin Endocrinol Metab, 2007 Dec;92:4853-64). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |