rs1060502301

Variant names:

• chr9-95458029-C-T
• rs1060502301
• NM_000264.5:c.3152G>A

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.3152G>A​(p.Trp1051*) variant causes a stop gained change involving the alteration of a conserved nucleotide. 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTCH1 NM_000264.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.48

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 9-95458029-C-T is Pathogenic according to our data. Variant chr9-95458029-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 409220.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCH1	NM_000264.5	c.3152G>A	p.Trp1051*	stop_gained	Exon 18 of 24	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3	c.3149G>A	p.Trp1050*	stop_gained	Exon 18 of 24	ENST00000437951.6	NP_001077072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11	c.3152G>A	p.Trp1051*	stop_gained	Exon 18 of 24	5	NM_000264.5	ENSP00000332353.6
PTCH1	ENST00000437951.6	c.3149G>A	p.Trp1050*	stop_gained	Exon 18 of 24	5	NM_001083603.3	ENSP00000389744.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PTCH1-related disorder Pathogenic:1

Nov 01, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PTCH1 c.3152G>A variant is predicted to result in premature protein termination (p.Trp1051*). This variant was reported to be causative for Gorlin syndrome (Sánchez-Vicente et al. 2016. PubMed ID: 27595027; Huq et al. 2017. PubMed ID: 28328109). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is classified as pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/409220/). Nonsense variants in PTCH1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Gorlin syndrome Pathogenic:1

Sep 08, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 409220). This premature translational stop signal has been observed in individuals with clinical features of basal cell nevus syndrome (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Trp1051*) 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). -

Hereditary cancer-predisposing syndrome Pathogenic:1

May 31, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.W1051* pathogenic mutation (also known as c.3152G>A), located in coding exon 18 of the PTCH1 gene, results from a G to A substitution at nucleotide position 3152. This changes the amino acid from a tryptophan to a stop codon at position 1051. 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	0.62	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
Vest4		0.96
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1060502301; hg19: chr9-98220311;