Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000166126 | SCV000216897 | pathogenic | Hereditary cancer-predisposing syndrome | 2019-04-04 | criteria provided, single submitter | clinical testing | The c.88delC pathogenic mutation, located in coding exon 2 of the SDHB gene, results from a deletion of one nucleotide at position 88, causing a translational frameshift with a predicted alternate stop codon. This alteration has been identified in multiple individuals in the literature who had a personal and/or family history of PGL/PCC (Benn DE et al. J. Med. Genet. 2018 Nov;55(11):729-734; Andrews KA et al. J. Med. Genet. 2018 Jun;55(6):384-394), including a 12-year-old male diagnosed with an abdominal PGL/PCC (Benn, DE et al. Oncogene. 2003 Mar 6;22(9):1358-64), and a 13-year-old male diagnosed with 3 simultaneous extra-adrenal PGLs whose tumor showed loss of heterozygosity (LOH) at the SDHB locus (Prasad P et al. Cancer Genet Cytogenet. 2009;192(2):82-85). This mutation has also been reported in an individual diagnosed with bilateral renal carcinoma at age 27. His unaffected mother was also a carrier and there was no known family history of PGL/PCC (Paik, JY et al. J Clin Oncol. 2014 Feb 20;32(6):e10-3). Functional studies of this alteration have demonstrated the absence of SDH enzymatic activity as well as the absence of SDHB protein in cell-based assays when compared to wildtype, indicating nonsense-mediated mRNA decay or protein degradation as a mechanism for absent enzymatic activity (Kim E, Endocr. Relat. Cancer 2015 Jun; 22(3):387-97). In addition to the clinical and functional data presented in the literature, since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation. |
| Labcorp Genetics |
RCV001058703 | SCV001223294 | pathogenic | Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma | 2022-06-17 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Gln30Argfs*47) in the SDHB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SDHB are known to be pathogenic (PMID: 19454582, 19802898). This variant is present in population databases (rs747198089, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with clinical features of hereditary paraganglioma-pheochromocytoma (PGL-PCC) syndrome (PMID: 12618761, 19596260, 24395865). ClinVar contains an entry for this variant (Variation ID: 186518). For these reasons, this variant has been classified as Pathogenic. |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV004998345 | SCV005624039 | pathogenic | not provided | 2024-04-12 | criteria provided, single submitter | clinical testing | The SDHB c.88del (p.Gln30Argfs*47) variant alters the translational reading frame of the SDHB mRNA and causes the premature termination of SDHB protein synthesis. This variant has been reported in the published literature in in individuals with hereditary paraganglioma-pheochromocytoma (PGL-PCC) syndrome (PMID: 12618761 (2003), 19454582 (2009), 19596260 (2009), 23072324 (2013)) and renal cell carcinoma (PMID: 24395865 (2014)). The frequency of this variant in the general population, 0.000032 (1/30914 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. |
| Section on Medical Neuroendocrinolgy, |
RCV000505352 | SCV000599485 | pathogenic | Hereditary pheochromocytoma-paraganglioma | no assertion criteria provided | research |