rs864622212

Positions:

• chr9-95506541-AAG-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.258_259del​(p.Leu87IlefsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 2.60

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]

(HGNC:):

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 9-95506541-AAG-A is Pathogenic according to our data. Variant chr9-95506541-AAG-A is described in ClinVar as [Pathogenic]. Clinvar id is 219697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95506541-AAG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTCH1	NM_000264.5	c.258_259del	p.Leu87IlefsTer2	frameshift_variant	2/24	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3	c.255_256del	p.Leu86IlefsTer2	frameshift_variant	2/24	ENST00000437951.6	NP_001077072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11	c.258_259del	p.Leu87IlefsTer2	frameshift_variant	2/24	5	NM_000264.5	ENSP00000332353	A2
PTCH1	ENST00000437951.6	c.255_256del	p.Leu86IlefsTer2	frameshift_variant	2/24	5	NM_001083603.3	ENSP00000389744
	ENST00000604104.1	n.310_311del		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gorlin syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 05, 2022

This sequence change creates a premature translational stop signal (p.Leu87Ilefs*2) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 219697). This premature translational stop signal has been observed in individuals with nevoid basal cell carcinoma syndrome (PMID: 8981943, 16301862). This variant is not present in population databases (gnomAD no frequency). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 09, 2016

The c.258_259delCT pathogenic variant in the PTCH gene has been reported previously in association with Gorlin syndrome using different numbering (Wicking et al., 1997). This deletion causes a frameshift starting with codon Leucine 87, changes this amino acid to an Isoleucine residue and creates a premature Stop codon at position 2 of the new reading frame, denoted p.Leu87IlefsX2. The c.258_259delCT variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. It is predicted to result in nonsense-mediated mRNA decay or in premature protein truncation. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 15, 2020

The c.258_259delCT pathogenic mutation, located in coding exon 2 of the PTCH1 gene, results from a deletion of two nucleotides at nucleotide positions 258 to 259, causing a translational frameshift with a predicted alternate stop codon (p.L87Ifs*2). This alteration has been reported in several individuals diagnosed with nevoid basal cell-carcinoma (NBCCS) (Wicking C et al. Am J Hum Genet. 1997 Jan;60(1):21-6; Klein RD et al. Genet Med. 2005 Nov-Dec;7(9):611-9; Alonso N et al. Br. J. Dermatol. 2018 01;178:198-206). This alteration was also reported in a 12-year-old female with epiretinal membrane in the right eye and bilateral myelinated nerve fiber layer, pathologically confirmed basal cell carcinomas, and multiple odontogenic keratocysts of the jaw (Farley ND et al. Retin Cases Brief Rep. 11 Suppl 1:S151-S154). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Holoprosencephaly 7 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

3billion

-

The variant is not observed in the gnomAD v2.1.1 dataset. The variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000219697 / PMID: 8981943). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

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: rs864622212; hg19: chr9-98268823;