ClinVar

Description

​<span style="background-color:initial">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 <span style="background-color:initial">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)<span style="background-color:initial">. 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.