9-95476835-C-T

Variant names:

• chr9-95476835-C-T
• rs1060502268
• NM_000264.5:c.1526G>A

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.1526G>A​(p.Gly509Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G509V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PTCH1 NM_000264.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.39

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 helix (size 8) in uniprot entity PTC1_HUMAN there are 7 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, 0.986
• PP5: Variant 9-95476835-C-T is Pathogenic according to our data. Variant chr9-95476835-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 409140.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95476835-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCH1	NM_000264.5	c.1526G>A	p.Gly509Asp	missense_variant	Exon 11 of 24	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3	c.1523G>A	p.Gly508Asp	missense_variant	Exon 11 of 24	ENST00000437951.6	NP_001077072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11	c.1526G>A	p.Gly509Asp	missense_variant	Exon 11 of 24	5	NM_000264.5	ENSP00000332353.6
PTCH1	ENST00000437951.6	c.1523G>A	p.Gly508Asp	missense_variant	Exon 11 of 24	5	NM_001083603.3	ENSP00000389744.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461710 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727154

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Apr 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 509 of the PTCH1 protein (p.Gly509Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Gorlin syndrome (PMID: 12655573, 16088933, 16301862, 24204797). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 409140). 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) performed at Invitae indicates that this missense variant is expected to disrupt PTCH1 protein function with a positive predictive value of 95%. This variant disrupts the p.Gly509 amino acid residue in PTCH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8840969, 12192414, 15042702, 15712338). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Dec 21, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G509D pathogenic mutation (also known as c.1526G>A), located in coding exon 11 of the PTCH1 gene, results from a G to A substitution at nucleotide position 1526. The glycine at codon 509 is replaced by aspartic acid, an amino acid with similar properties. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported in numerous individuals diagnosed with nevoid basal cell carcinoma syndrome (NBCCS) (Fujii K et al. Hum. Mutat. 2003; 21:451-2, Nagao K et al. Hum. Mol. Genet. 2005; 14:3379-88, Klein RD et al. Genet. Med. 2005; 7(9):611-9, Marsh A et al. Hum. Mutat. 2005 Sep;26(3):283, Guo YY et al. PLoS ONE 2013; 8:e77305, Hong YJ et al. Bone Miner. Res. 2016 07;31(7):1413-28, Reinders MG et al. Mol Genet Genomic Med. 2018 05;6(3):409-415). In one of these individuals, this alteration was detected as a de novo finding (Marsh A et al. Hum. Mutat. 2005 Sep;26(3):283). 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	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.;.;.;.;.;.;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;.;D;D;.;.;D;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.96	D
PROVEAN	Pathogenic	-6.1	D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;.
Polyphen		1.0	D;D;D;D;D;D;D;.
Vest4		0.99
MutPred		0.95		Gain of sheet (P = 0.1451);.;.;.;.;.;.;.;
MVP		0.93
MPC		1.7
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.99

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: rs1060502268; hg19: chr9-98239117; COSMIC: COSV59465449; COSMIC: COSV59465449;