ClinVar Miner

Submissions for variant NM_000264.5(PTCH1):c.394+1G>A

dbSNP: rs1131690995
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492083 SCV000581065 pathogenic Hereditary cancer-predisposing syndrome 2023-03-07 criteria provided, single submitter clinical testing The c.394+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 2 of the PTCH1 gene. This alteration has been observed in at least one individual with a personal and/or family history that is consistent with PTCH1-related disease (Ambry internal data). In addition, this variant has been determined to be the result of a de novo mutation or germline mosaicism in one individual with Nevoid basal cell carcinoma syndrome (Ambry internal data). 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; however, direct evidence is insufficient at this time (Ambry internal data). 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. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx RCV000578764 SCV000680602 pathogenic not provided 2017-04-12 criteria provided, single submitter clinical testing This variant is denoted PTCH1 c.394+1G>A or IVS2+1G>A and consists of a G>A nucleotide substitution at the +1 position of intron 2 of the PTCH1 gene. This variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has not, to our knowledge, been published in the literature. Based on the current evidence, we consider this variant to be pathogenic.
Invitae RCV001208405 SCV001379789 pathogenic Gorlin syndrome 2023-07-04 criteria provided, single submitter clinical testing Disruption of this splice site has been observed in individuals with clinical features of basal cell nevus syndrome (PMID: 29575684, 30997576; Invitae). For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 2 and introduces a premature termination codon (PMID: 30997576). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 428849). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 2 of the PTCH1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product.

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