rs1554695039

Positions:

• chr9-95468939-G-A
• chr9-95468939-G-C
• chr9-95468939-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.2062C>T​(p.Gln688Ter) 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:2
• Conservation: PhyloP100: 9.44

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 9-95468939-G-A is Pathogenic according to our data. Variant chr9-95468939-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 453812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95468939-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTCH1	NM_000264.5	c.2062C>T	p.Gln688Ter	stop_gained	14/24	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3	c.2059C>T	p.Gln687Ter	stop_gained	14/24	ENST00000437951.6	NP_001077072.1
LOC100507346	NR_038982.1	n.877G>A		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11	c.2062C>T	p.Gln688Ter	stop_gained	14/24	5	NM_000264.5	ENSP00000332353	A2
PTCH1	ENST00000437951.6	c.2059C>T	p.Gln687Ter	stop_gained	14/24	5	NM_001083603.3	ENSP00000389744

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 20, 2018

This variant has been reported in an individual affected with nevoid basal cell carcinoma syndrome (PMID: 8981943, 22952776). ClinVar contains an entry for this variant (Variation ID: 45381). For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in PTCH1 are known to be pathogenic (PMID: 16301862, 16419085). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln688*) in the PTCH1 gene. It is expected to result in an absent or disrupted protein product. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 30, 2022

The p.Q688* pathogenic mutation (also known as c.2062C>T), located in coding exon 14 of the PTCH1 gene, results from a C to T substitution at nucleotide position 2062. This changes the amino acid from a glutamine to a stop codon within coding exon 14. This mutation was identified in one individual out of a cohort of 71 unrelated individuals with nevoid basal cell carcinoma syndrome (NBCCS) (Wicking C et al. Am J Hum Genet, 1997 Jan;60:21-6). This mutation was also identified in a patient with a history of keratocystic odontogenic tumor, >10 basal cell carcinomas, and bifid rib who had a daughter with polydactaly and bifid rib (Pastorino L et al. PLoS One, 2012 Aug;7:e43827). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A
Vest4		0.96
GERP RS		4.8

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: rs1554695039; hg19: chr9-98231221; COSMIC: COSV59462204;