Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000164884 | SCV000215570 | uncertain significance | Hereditary cancer-predisposing syndrome | 2018-07-24 | criteria provided, single submitter | clinical testing | The p.L65F variant (also known as c.193C>T), located in coding exon 2 of the SDHB gene, results from a C to T substitution at nucleotide position 193. The leucine at codon 65 is replaced by phenylalanine, an amino acid with highly similar properties. Alterations at the same codon (p.L65R, p.L65H, p.L65H) have been reported in patients with pheochromocytomas and/or paragangliomas. 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 at this time, the clinical significance of p.L65F remains unclear. |
| Labcorp Genetics |
RCV000560019 | SCV000630696 | uncertain significance | Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma | 2024-12-17 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 65 of the SDHB protein (p.Leu65Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant SDHB-related conditions (PMID: 34439371, 34906457; internal data). ClinVar contains an entry for this variant (Variation ID: 185456). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SDHB protein function with a negative predictive value of 80%. This variant disrupts the p.Leu65 amino acid residue in SDHB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15328326, 22835832; internal data). 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. |
| Fulgent Genetics, |
RCV002485021 | SCV002799517 | uncertain significance | Gastrointestinal stromal tumor; Carney-Stratakis syndrome; Paragangliomas 4; Pheochromocytoma; Mitochondrial complex 2 deficiency, nuclear type 4 | 2021-07-16 | criteria provided, single submitter | clinical testing | |
| All of Us Research Program, |
RCV003995373 | SCV004817933 | uncertain significance | Hereditary pheochromocytoma-paraganglioma | 2023-02-24 | criteria provided, single submitter | clinical testing | This missense variant replaces leucine with phenylalanine at codon 65 of the SDHB protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hereditary paranganglioma-pheochromocytoma syndrome (PMID: 34439371). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |