ClinVar Miner

Submissions for variant NM_001083602.2(PTCH1):c.1405-2A>G (rs1064793921)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000483991 SCV000567352 pathogenic not provided 2015-07-23 criteria provided, single submitter clinical testing The c.1603-2 A>G splice site variant in the PTCH1 gene destroys the canonical spliceacceptor site in intron 11. It is predicted to cause abnormal gene splicing, either leading toan abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormalprotein product if the message is used for protein translation. Although this exact variant has not previously been reported to our knowledge, another splice site variant at this samenucleotide position (c.1603-2 A>C) has been reported in HGMD in association with nevoidbasal cell carcinoma syndrome (Stenson et al., 2014). Therefore, we consider the c.1603-2 A>G variant to be pathogenic.
Invitae RCV000543539 SCV000622923 pathogenic Gorlin syndrome 2018-10-20 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 11 of the PTCH1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PTCH1-related disease. ClinVar contains an entry for this variant (Variation ID: 419508). 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. A different variant affecting this nucleotide (c.1603-2A>C) has been determined to be pathogenic (PMID: 24814739). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PTCH1 are known to be pathogenic (PMID: 16301862, 16419085). For these reasons, this variant has been classified as Pathogenic.

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