rs1554708771

chr9-95506545-GTC-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000264.5(PTCH1):c.254_255del(p.Arg85ThrfsTer4) variant causes a frameshift change. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R85R) has been classified as Likely 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: 3.69

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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 9-95506545-GTC-G is Pathogenic according to our data. Variant chr9-95506545-GTC-G is described in ClinVar as [Pathogenic]. Clinvar id is 524519.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95506545-GTC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTCH1	NM_000264.5	c.254_255del	p.Arg85ThrfsTer4	frameshift_variant	2/24	ENST00000331920.11
PTCH1	NM_001083603.3	c.251_252del	p.Arg84ThrfsTer4	frameshift_variant	2/24	ENST00000437951.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTCH1	ENST00000331920.11	c.254_255del	p.Arg85ThrfsTer4	frameshift_variant	2/24	5	NM_000264.5	A2
PTCH1	ENST00000437951.6	c.251_252del	p.Arg84ThrfsTer4	frameshift_variant	2/24	5	NM_001083603.3
	ENST00000604104.1	n.315_316del		non_coding_transcript_exon_variant	1/1

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:2

Pathogenic, criteria provided, single submitter	research	Duke University Health System Sequencing Clinic, Duke University Health System	Apr 20, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 01, 2018	This sequence change creates a premature translational stop signal (p.Arg85Thrfs*4) in the PTCH1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with nevoid basal cell carcinoma syndrome (PMID: 16088933). Loss-of-function variants in PTCH1 are known to be pathogenic (PMID: 16301862, 16419085). For these reasons, this variant has been classified as Pathogenic. -

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: rs1554708771; hg19: chr9-98268827;