rs1554698582

chr9-95477617-GCAACCAGCAGGACGC-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM4 PP3 PP5_Moderate

The NM_000264.5(PTCH1):c.1418_1432del(p.Gly473_Val477del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. G473G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTCH1 NM_000264.5 inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• 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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a helix (size 23) in uniprot entity PTC1_HUMAN there are 11 pathogenic changes around while only 2 benign (85%) in NM_000264.5
• PM4: Nonframeshift variant in NON repetitive region in NM_000264.5.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 9-95477617-GCAACCAGCAGGACGC-G is Pathogenic according to our data. Variant chr9-95477617-GCAACCAGCAGGACGC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 453786.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTCH1	NM_000264.5	c.1418_1432del	p.Gly473_Val477del	inframe_deletion	10/24	ENST00000331920.11
PTCH1	NM_001083603.3	c.1415_1429del	p.Gly472_Val476del	inframe_deletion	10/24	ENST00000437951.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTCH1	ENST00000331920.11	c.1418_1432del	p.Gly473_Val477del	inframe_deletion	10/24	5	NM_000264.5	A2
PTCH1	ENST00000437951.6	c.1415_1429del	p.Gly472_Val476del	inframe_deletion	10/24	5	NM_001083603.3

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: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Gorlin syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 12, 2017

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This in-frame deletion of 5 amino acids (Gly473-Val477) occurs within the third transmembrane domain (amino acids 473-498) of the PTCH1 protein (PMID: 16419085, 17021131, 8658145, 8981943). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acids is currently unknown. Family studies have indicated that this variant was not present in the parents of an individual affected with Gorlin syndrome, which suggests that it was de novo in that affected individual (Invitae). This variant is not present in population databases (ExAC no frequency). This variant, c.1418_1432delGCGTCCTGCTGGTTG, results in the deletion of 5 amino acids of the PTCH1 protein (p.Gly473_Val477del), but otherwise preserves the integrity of the reading frame. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554698582; hg19: chr9-98239899;