Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000570334 | SCV000664569 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-05-26 | criteria provided, single submitter | clinical testing | The c.314+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 3 of the SDHD gene. This mutation has been identified in an individual with multiple paragangliomas (Ambry internal data). Different alterations at the same nucleotide position (c.314+1G>A and c.314+1G>C) have also been reported in individuals with paragangliomas (Benn DE et al. J. Clin. Endocrinol. Metab. 2006 Mar;91:827-36; Persu A et al. J. Hypertens. 2008 Jul;26:1395-401). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. 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 a disease-causing mutation. |
| Labcorp Genetics |
RCV002231524 | SCV001227185 | pathogenic | Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas with sensorineural hearing loss; Cowden syndrome 3 | 2023-07-14 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 3 of the SDHD gene. While this variant 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 (gnomAD no frequency). Disruption of this splice site has been observed in individuals with paraganglioma-pheochromocytoma syndromes (PMID: 16317055, 18551016; Invitae). ClinVar contains an entry for this variant (Variation ID: 480808). 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 disrupts a region of the SDHD protein in which other variant(s) (p.Gly138Arg) have been determined to be pathogenic (PMID: 29875428, 31492822; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |