Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000215647 | SCV000277743 | pathogenic | Hereditary cancer-predisposing syndrome | 2015-08-11 | criteria provided, single submitter | clinical testing | The c.642_642+6DdelGGTGAGG pathogenic mutation results from a deletion of the last nucleotide of exon 6 and six nucleotides after coding exon 6 in the SDHB gene. This mutation is predicted to remove the canonical splice sequence as well as create a disruption within the reading frame. This mutation was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this mutation was not observed in 6497 samples (12994 alleles) with coverage at this position. To date, this mutation has been detected with an allele frequency of approximately 0.02% (greater than 6100 alleles tested) in our clinical cohort. These nucleotide positions are highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native donor splice site. Based on the available evidence, c.642_642+6delGGTGAGG is classified as a pathogenic mutation. |
| Labcorp Genetics |
RCV001854690 | SCV002306639 | likely pathogenic | Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma | 2022-02-23 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 233382). 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. Variants that disrupt 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. This variant has not been reported in the literature in individuals affected with SDHB-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a splice site in intron 6 of the SDHB gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SDHB are known to be pathogenic (PMID: 19454582, 19802898). |