rs1060502292

chr9-95468802-TGA-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.2197_2198del(p.Ser733IlefsTer4) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S733S) has been classified as Benign. 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:2
• Conservation: PhyloP100: 9.21

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]

LOC100507346 (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 9-95468802-TGA-T is Pathogenic according to our data. Variant chr9-95468802-TGA-T is described in ClinVar as [Pathogenic]. Clinvar id is 409193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95468802-TGA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTCH1	NM_000264.5	c.2197_2198del	p.Ser733IlefsTer4	frameshift_variant	14/24	ENST00000331920.11
PTCH1	NM_001083603.3	c.2194_2195del	p.Ser732IlefsTer4	frameshift_variant	14/24	ENST00000437951.6
LOC100507346	NR_038982.1	n.744_745del		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTCH1	ENST00000331920.11	c.2197_2198del	p.Ser733IlefsTer4	frameshift_variant	14/24	5	NM_000264.5	A2
PTCH1	ENST00000437951.6	c.2194_2195del	p.Ser732IlefsTer4	frameshift_variant	14/24	5	NM_001083603.3

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gorlin syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 20, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 409193). This variant is also known as 2183delTC. This premature translational stop signal has been observed in individual(s) with nevoid basal cell carcinoma syndrome (NBCCS) (PMID: 8981943, 16301862, 16419085). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser733Ilefs*4) 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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 04, 2014

​The c.2197_2198delTC pathogenic mutation, located in coding exon 14 of the PTCH1 gene, results from a deletion of 2 nucleotides between positions 2197 and 2198, causing a translational frameshift with a predicted alternate stop codon. This mutation was identified in an individual meeting NBCCS clinical criteria (Wicking, C et al. Am J Hum Genet. 1997 Jan;60(1):21-6). Note, this mutation is called 2183delTC in this publication. In addition to the clinical data presented in the literature, since frameshifts 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

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: rs1060502292; hg19: chr9-98231084;