Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000492191 | SCV000581051 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2016-01-06 | criteria provided, single submitter | clinical testing | The p.L1135P variant (also known as c.3404T>C), located in coding exon 20 of the PTCH1 gene, results from a T to C substitution at nucleotide position 3404. The leucine at codon 1135 is replaced by proline, an amino acid with similar properties. This alteration was detected in an individual satisfying diagnostic criteria for Nevoid basal cell-carcinoma syndrome (Ambry internal data). In addition, based on internal structural analysis, this variant is anticipated to severely impact the structure of the transmembrane helix. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Invitae | RCV001036728 | SCV001200105 | uncertain significance | Gorlin syndrome | 2019-12-13 | criteria provided, single submitter | clinical testing | 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with PTCH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 428842). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 1135 of the PTCH1 protein (p.Leu1135Pro). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and proline. |