Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000166877 | SCV000217693 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2018-07-11 | criteria provided, single submitter | clinical testing | The p.D138Y variant (also known as c.412G>T), located in coding exon 4 of the SDHB gene, results from a G to T substitution at nucleotide position 412. The aspartic acid at codon 138 is replaced by tyrosine, an amino acid with highly dissimilar properties. A different variant at the same position (p.D138N, c.412G>A) has been reported in two individuals with paraganglioma and tumor studies for these individuals revealed absent SDHB expression on immunohistochemistry (Lefebvre S et al. Horm. Metab. Res. 2012 May;44:334-8; Nozières C et al. Eur. J. Endocrinol. 2012 Jun;166:1107-11). Structural analysis showed that D138 engages in hydrogen bonds and electrostatic interactions with nearby residues and D138Y results in local destabilization of the SDHB protein (Sun F et al. Cell. 2005 Jul;121:1043-57; Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature. 2016 08;536:285-91). 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. |
| Laboratory of Medical Genetics, |
RCV001729423 | SCV001976794 | likely pathogenic | Paragangliomas 4 | 2021-08-10 | criteria provided, single submitter | clinical testing | PM2, PM5, PP2, PP3, PP5 |
| Labcorp Genetics |
RCV001850356 | SCV002307241 | likely pathogenic | Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma | 2020-12-12 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid with tyrosine at codon 138 of the SDHB protein (p.Asp138Tyr). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SDHB-related conditions. ClinVar contains an entry for this variant (Variation ID: 187177). 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 expected to disrupt SDHB protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.Asp138 amino acid residue in SDHB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22517554, 31666924, 31492822). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |