ClinVar Miner

Submissions for variant NM_001083603.3(PTCH1):c.4del (p.Glu2fs)

dbSNP: rs752765582
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Paul Sabatier University EA-4555, Paul Sabatier University RCV000207438 SCV000259119 likely pathogenic Anophthalmia-microphthalmia syndrome 2013-01-01 criteria provided, single submitter clinical testing rare variant, functional studies demonstrating is deleterious effect on protein.
New York Genome Center RCV002227460 SCV002506703 uncertain significance Gorlin syndrome; Holoprosencephaly 7 2021-06-07 criteria provided, single submitter clinical testing The inherited heterozygous PTCH1 variant c.4delG (p.Glu2AsnfsTer9) is localized in coding exon 1 of 23 which is unique to one of the longer transcripts (NM_001083603.2, isoform L′ from transcript 1a′; PMID: 29930296). This isoform was previously found to be expressed at very low levels in multiple human tissues (PMID: 15780749). In the other longer PTCH1 transcripts, this variant is present in the non-coding 5’ UTR region. This variant is predicted to alter the translational reading frame and cause loss of normal protein function either through protein truncationor nonsense-mediated mRNA decay. The c.4delG variant has been reported once in an individual with ocular anomalies - microphthalmia, cataract, and sclerocornea (PMID: 26893459). Ocular developmental anomalies can be seen as part of both the basal cell nevus syndrome and Holoprosencephaly phenotypes. This variant is present at a very low frequency (0.00002630, 4/152118 heterozygous alleles, no homozygotes) in gnomAD v3 indicating it is not a common benign variant in the populations represented in this database. Due to lack of additional genetic and functional evidence, the inherited heterozygous c.4delG (p.Glu2AsnfsTer9) variant seen in one of the alternate exons unique to a single transcript of PTCH1 gene is reported as a variant of uncertain significance.
Sema4, Sema4 RCV002258831 SCV002536451 likely benign Hereditary cancer-predisposing syndrome 2021-06-14 criteria provided, single submitter curation
MGZ Medical Genetics Center RCV002288834 SCV002581541 likely pathogenic Gorlin syndrome 2022-03-08 criteria provided, single submitter clinical testing

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