rs1064794260

Variant names:

• chr9-95459654-G-A
• rs1064794260
• NM_000264.5:c.2833C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-95459654-G-A
• chr9-95459654-G-C
• chr9-95459654-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000264.5(PTCH1):​c.2833C>T​(p.Arg945*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PTCH1 NM_000264.5 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 5.32

Genes affected

PTCH1 (HGNC:9585): (patched 1) This gene encodes a member of the patched family of proteins and a component of the hedgehog signaling pathway. Hedgehog signaling is important in embryonic development and tumorigenesis. The encoded protein is the receptor for the secreted hedgehog ligands, which include sonic hedgehog, indian hedgehog and desert hedgehog. Following binding by one of the hedgehog ligands, the encoded protein is trafficked away from the primary cilium, relieving inhibition of the G-protein-coupled receptor smoothened, which results in activation of downstream signaling. Mutations of this gene have been associated with basal cell nevus syndrome and holoprosencephaly. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-95459654-G-A is Pathogenic according to our data. Variant chr9-95459654-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 420053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95459654-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCH1	NM_000264.5	c.2833C>T	p.Arg945*	stop_gained	Exon 17 of 24	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3	c.2830C>T	p.Arg944*	stop_gained	Exon 17 of 24	ENST00000437951.6	NP_001077072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11	c.2833C>T	p.Arg945*	stop_gained	Exon 17 of 24	5	NM_000264.5	ENSP00000332353.6
PTCH1	ENST00000437951.6	c.2830C>T	p.Arg944*	stop_gained	Exon 17 of 24	5	NM_001083603.3	ENSP00000389744.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Sep 10, 2021

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 07, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (Lek et al., 2016); Also known as c.2821C>T, p.R944X; This variant is associated with the following publications: (PMID: 10200051, 34291140, 27535533, 9654212, 24204797, 25525159) -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Gorlin syndrome Pathogenic:2

Jun 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. Loss-of-function variants in PTCH1 are known to be pathogenic (PMID: 16301862, 16419085). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with basal cell nevus syndrome (PMID: 10200051). This variant is also known as C2821T. ClinVar contains an entry for this variant (Variation ID: 420053). For these reasons, this variant has been classified as Pathogenic. -

Nov 06, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Jul 06, 2015

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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 an arginine to a stop codon within coding exon 17. This alteration was previously identified in one individual with nevoid basal cell carcinoma syndrome (NBCCS), presenting with jaw cysts, bifid ribs, scoliosis, kyphosis, hypertelorism, and numerous basal cell carcinomas on the face, scalp, and trunk (Hasenpusch-Theil K, 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.96	D
Vest4		0.93
GERP RS		2.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1064794260; hg19: chr9-98221936; COSMIC: COSV105239322;