ClinVar Miner

Submissions for variant NM_000264.5(PTCH1):c.2833C>T (p.Arg945Ter) (rs1064794260)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000479378 SCV000568527 pathogenic not provided 2016-11-22 criteria provided, single submitter clinical testing This variant is denoted PTCH1 c.2833C>T at the cDNA level and p.Arg945Ter (R945X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been observed in an individual with a clinical diagnosis of Gorlin syndrome (Hasenpusch-Theil 1998) and is considered pathogenic.
Ambry Genetics RCV000492276 SCV000581037 pathogenic Hereditary cancer-predisposing syndrome 2015-07-06 criteria provided, single submitter clinical testing The p.R945* pathogenic mutation (also known as c.2833C>T) located in coding exon 17 of the PTCH1 gene, results from a C to T substitution at nucleotide position 2833. This changes the amino acid from anarginineto a stopcodonwithin codingexon17.This alteration was previously identified in one individual with nevoid basal cellcarcinoma syndrome (NBCCS), presenting with jaw cysts, bifid ribs, scoliosis, kyphosis, hypertelorism, and numerous basal cell carcinomas on the face, scalp, and trunk (Hasenpusch-TheilK, Hum.Mutat. 1998; 11(6):480).In addition to the clinical data presented in the literature, since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).
Invitae RCV001216304 SCV001388094 pathogenic Gorlin syndrome 2020-10-24 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg945*) in the PTCH1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with basal cell nevus syndrome (PMID: 10200051). This variant is also known as C2821T in the literature. ClinVar contains an entry for this variant (Variation ID: 420053). Loss-of-function variants in PTCH1 are known to be pathogenic (PMID: 16301862, 16419085). For these reasons, this variant has been classified as Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000479378 SCV001447206 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001216304 SCV001448584 likely pathogenic Gorlin syndrome 2020-11-06 criteria provided, single submitter clinical testing Variant summary: PTCH1 c.2833C>T (p.Arg945X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251486 control chromosomes. c.2833C>T has been reported in the literature in at least an individual affected with Nevoid Basal Cell Carcinoma Syndrome (NBCCS, Gorlin Syndrome) (Hasenpusch-Theil_1997). The variant was also reported in a family suffering from orofacial cleft and suspected to be affected by NBCCS (Zhong_2019). The authors of this report speculated on the pathology based on the results of bioinformatics and biochemical assays but suggested that further cellular and molecular studies were needed to confirm the diagnosis of NBCCS. In in vitro functional assays, the variant showed approximately 75% lower relative abundance, implying a decrease in the stability of R945X mutant in vitro (Zhong_2019). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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