rs1131690983

Variant names:

• chr9-95469814-T-C
• rs1131690983
• NM_000264.5:c.1846A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000264.5(PTCH1):​c.1846A>G​(p.Ser616Gly) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTCH1 NM_000264.5 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 5.74

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 9-95469814-T-C is Pathogenic according to our data. Variant chr9-95469814-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 428836.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCH1	NM_000264.5	c.1846A>G	p.Ser616Gly	missense_variant, splice_region_variant	Exon 13 of 24	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3	c.1843A>G	p.Ser615Gly	missense_variant, splice_region_variant	Exon 13 of 24	ENST00000437951.6	NP_001077072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11	c.1846A>G	p.Ser616Gly	missense_variant, splice_region_variant	Exon 13 of 24	5	NM_000264.5	ENSP00000332353.6
PTCH1	ENST00000437951.6	c.1843A>G	p.Ser615Gly	missense_variant, splice_region_variant	Exon 13 of 24	5	NM_001083603.3	ENSP00000389744.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Mar 06, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S616G pathogenic mutation (also known as c.1846A>G), located in coding exon 13 of the PTCH1 gene, results from an A to G substitution at nucleotide position 1846. The serine at codon 616 is replaced by glycine, an amino acid with similar properties. This variant has been observed in multiple individuals with a personal and/or family history that is consistent with nevoid basal cell carcinoma syndrome (Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Gorlin syndrome Uncertain:1

Oct 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 616 of the PTCH1 protein (p.Ser616Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PTCH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 428836). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PTCH1 protein function with a negative predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D;.;.;.;.;.;.;.
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T;.;T;T;.;.;T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.57	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Benign	1.6	L;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.0	N;N;N;N;N;N;N;N
REVEL	Uncertain	0.64
Sift	Benign	0.050	D;T;T;T;T;T;T;T
Sift4G	Benign	0.16	T;T;T;T;T;T;T;.
Polyphen		0.48	P;P;P;B;B;P;P;.
Vest4		0.29
MutPred		0.60		Loss of stability (P = 0.0763);.;.;.;.;.;.;.;
MVP		0.75
MPC		0.51
ClinPred		0.82	D
GERP RS		5.4
Varity_R		0.24
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.69		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.69		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1131690983; hg19: chr9-98232096; COSMIC: COSV105238999; COSMIC: COSV105238999;