ClinVar Miner

Submissions for variant NM_003002.4(SDHD):c.314+1G>T (rs1555187083)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000570334 SCV000664569 pathogenic Hereditary cancer-predisposing syndrome 2019-01-24 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). 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.
Invitae RCV001062388 SCV001227185 likely pathogenic Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas 1; Cowden syndrome 3 2019-05-18 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). Disruptions of this splice site, also known as IVS3+1, have been observed in several individuals affected with paraganglioma-pheochromocytoma syndromes (PMID: 16317055, 18551016, Invitae). ClinVar contains an entry for this variant (Variation ID: 480808). 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.

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