Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000806583 | SCV000946588 | likely pathogenic | Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas 1; Cowden syndrome 3 | 2018-10-09 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in the last intron (intron 3) of the SDHD gene. While this is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (ExAC no frequency). Disruption of the splice site has been observed in several individuals and families affected with paraganglioma (PMID: 16317055, 19454582, 18551016, 19351833). ClinVar contains an entry for this variant (Variation ID: 438436). 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. 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. |
| Ambry Genetics | RCV001018787 | SCV001180064 | pathogenic | Hereditary cancer-predisposing syndrome | 2018-04-23 | criteria provided, single submitter | clinical testing | The c.314+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 3 of the SDHD gene. This alteration has been previously identified in a kindred with head and neck paragangliomas (Benn DE et al. J. Clin. Endocrinol. Metab., 2006 Mar;91:827-36). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. |
| Section on Medical Neuroendocrinolgy, |
RCV000505333 | SCV000599542 | pathogenic | Hereditary Paraganglioma-Pheochromocytoma Syndromes | no assertion criteria provided | research |