rs878853856

Positions:

• chr9-95453533-A-G
• chr9-95453533-A-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000264.5(PTCH1):​c.3394T>C​(p.Ser1132Pro) variant causes a missense 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1132Y) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PTCH1 NM_000264.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.73

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.

• PM1: In a transmembrane_region Helical (size 19) in uniprot entity PTC1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000264.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 9-95453533-A-G is Pathogenic according to our data. Variant chr9-95453533-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 237478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95453533-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTCH1	NM_000264.5	c.3394T>C	p.Ser1132Pro	missense_variant	20/24	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3	c.3391T>C	p.Ser1131Pro	missense_variant	20/24	ENST00000437951.6	NP_001077072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11	c.3394T>C	p.Ser1132Pro	missense_variant	20/24	5	NM_000264.5	ENSP00000332353.6
PTCH1	ENST00000437951.6	c.3391T>C	p.Ser1131Pro	missense_variant	20/24	5	NM_001083603.3	ENSP00000389744.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gorlin syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 15, 2023	This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 1132 of the PTCH1 protein (p.Ser1132Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with a personal and/or family history of basal cell nevus syndrome (PMID: 11231326, 23951062; Invitae). ClinVar contains an entry for this variant (Variation ID: 237478). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PTCH1 protein function. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 14, 2022	Variant summary: PTCH1 c.3394T>C (p.Ser1132Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251354 control chromosomes. c.3394T>C has been reported in the literature in individuals affected with Nevoid Basal Cell Carcinoma Syndrome (Gorlin Syndrome) (e.g. Reifenberger_2001, Shimada_2013, Morita_2015). These data indicate that the variant may be associated with disease. Co-occurrence with a pathogenic variant has been reported (BRCA1 c.848ins817-847). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported, however, another amino acid change located at the same codon (p.Ser1132Tyr in Chidambaram_1996) has been reported in association with Nevoid Basal Cell Carcinoma Syndrome suggesting the functional relevance of this residue to overall protein function. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 13, 2024

The p.S1132P pathogenic mutation (also known as c.3394T>C), located in coding exon 20 of the PTCH1 gene, results from a T to C substitution at nucleotide position 3394. The serine at codon 1132 is replaced by proline, an amino acid with similar properties. This variant has been observed in multiple individual with a personal and/or family history that is consistent with Nevoid basal cell carcinoma syndrome (Reifenberger J et al. J Invest Dermatol, 2001 Mar;116:472-4; Shimada Y et al. PLoS One, 2013 Aug;8:e70995; Guo YY et al. PLoS One, 2013 Oct;8:e77305; Morita K et al. PLoS One, 2015 Nov;10:e0140480; Ambry internal data). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;.;.;.;.;.;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;.;D;D;.;.;D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.6	M;.;.;.;.;.;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.4	D;D;D;D;D;D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0020	D;D;D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;D;D;.;D
Vest4		0.99
MutPred		0.96		Gain of glycosylation at T1133 (P = 0.1617);.;.;.;.;.;.;
MVP		0.94
MPC		1.7
ClinPred		0.98	D
GERP RS		5.4
Varity_R		0.99
gMVP		1.0

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: rs878853856; hg19: chr9-98215815; COSMIC: COSV59465317; COSMIC: COSV59465317;