Total submissions: 1
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000531863 | SCV000630731 | likely pathogenic | Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma | 2018-06-19 | criteria provided, single submitter | clinical testing | 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. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant is not present in population databases (ExAC no frequency). This sequence change deletes 14 nucleotides from the exon/intron boundary of exon 7 of the SDHB gene, including nucleotides that affect the donor splice site in the last intron (intron 7). While this is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. A different variant affecting the donor splice site c.765+1G>A (also known as 899+1G>A) has been observed in an individual with malignant paraganglioma or pheochromocytoma (PMID: 15328326). In addition, truncations (p.Ile263Tyrfs*12, p.Ile263Serfs*13) that lie downstream of this variant have been determined to be likely pathogenic (Invitae). This suggests that disruption of this region of the SDHB protein is causative of disease. This variant has been observed in an individual with recurrent paragangliomas (Invitae). ClinVar contains an entry for this variant (Variation ID: 459171). |