ClinVar Miner

Submissions for variant NM_003002.4(SDHD):c.53-7_53-3del

dbSNP: rs1865650219
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002242230 SCV001505009 uncertain significance Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas with sensorineural hearing loss; Cowden syndrome 3 2020-06-01 criteria provided, single submitter clinical testing This variant has not been reported in the literature in individuals with SDHD-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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 falls in intron 1 of the SDHD gene. It does not directly change the encoded amino acid sequence of the SDHD protein, but it affects a nucleotide within the consensus splice site of the intron.
Ambry Genetics RCV002350572 SCV002646453 likely pathogenic Hereditary cancer-predisposing syndrome 2023-12-08 criteria provided, single submitter clinical testing The c.53-7_53-3delTCCTC intronic variant results from a deletion of 5 nucleotides within intron 1 of the SDHD gene. This variant has been detected in an individual with paragangliomas (Ambry internal data). In silico splice site analysis predicts that this alteration may weaken the native splice acceptor site. RNA studies have demonstrated that this alteration results in a transcript predicted to lead to a protein with an in-frame deletion of 39 amino acids; the impacted region is critical for protein function and a significant portion of the protein is affected (Ambry internal data). In addition, this variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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