ENST00000468211.6:c.543_549delCCTCCTG

Variant names:

• chr9-95481947-ACAGGAGG-A
• rs1554700574
• ENST00000468211.6:c.543_549delCCTCCTG

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The ENST00000468211.6(PTCH1):​c.543_549delCCTCCTG​(p.Leu182LysfsTer19) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. YLL181?) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTCH1 ENST00000468211.6 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.95

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 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 12 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-95481947-ACAGGAGG-A is Pathogenic according to our data. Variant chr9-95481947-ACAGGAGG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 524565.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCH1	NM_000264.5	c.741_746+1delCCTCCTG	p.Tyr247_Leu249delinsTer	stop_gained, splice_donor_variant, disruptive_inframe_deletion, splice_region_variant, intron_variant	Exon 5 of 24	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3	c.738_743+1delCCTCCTG	p.Tyr246_Leu248delinsTer	stop_gained, splice_donor_variant, disruptive_inframe_deletion, splice_region_variant, intron_variant	Exon 5 of 24	ENST00000437951.6	NP_001077072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11	c.741_746+1delCCTCCTG	p.Tyr247_Leu249delinsTer	stop_gained, splice_donor_variant, disruptive_inframe_deletion, splice_region_variant, intron_variant	Exon 5 of 24	5	NM_000264.5	ENSP00000332353.6
PTCH1	ENST00000437951.6	c.738_743+1delCCTCCTG	p.Tyr246_Leu248delinsTer	stop_gained, splice_donor_variant, disruptive_inframe_deletion, splice_region_variant, intron_variant	Exon 5 of 24	5	NM_001083603.3	ENSP00000389744.2

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

Aug 02, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). This sequence change affects the donor splice site in intron 5 of the PTCH1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant has not been reported in the literature in individuals with PTCH1-related disease. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PTCH1 are known to be pathogenic (PMID: 16301862, 16419085). 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. -

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: rs1554700574; hg19: chr9-98244229;