NM_000264.5(PTCH1):c.395-1G>A AND Gorlin syndrome

Germline classification:: Conflicting classifications of pathogenicity (4 submissions)
Last evaluated:: Jan 22, 2024
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000149897.19

Allele description [Variation Report for NM_000264.5(PTCH1):c.395-1G>A]

NM_000264.5(PTCH1):c.395-1G>A

Gene:

PTCH1:patched 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

9q22.32

Genomic location:

Preferred name:

NM_000264.5(PTCH1):c.395-1G>A

HGVS:

NC_000009.12:g.95485875C>T
NG_007664.1:g.36091G>A
NM_000264.5:c.395-1G>AMANE SELECT
NM_001083602.3:c.197-1G>A
NM_001083603.3:c.392-1G>A
NM_001083604.3:c.-59-1G>A
NM_001083605.3:c.-59-1G>A
NM_001083606.3:c.-59-1G>A
NM_001083607.3:c.-59-1G>A
NM_001354918.2:c.395-1G>A
NM_001354919.2:c.197-1G>A
LRG_515t1:c.395-1G>A
LRG_515:g.36091G>A
NC_000009.11:g.98248157C>T
NM_000264.3:c.395-1G>A
NM_000264.4:c.395-1G>A

Links:

dbSNP: rs368869806

NCBI 1000 Genomes Browser:

rs368869806

Molecular consequence:

NM_000264.5:c.395-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001083602.3:c.197-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001083603.3:c.392-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001083604.3:c.-59-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001083605.3:c.-59-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001083606.3:c.-59-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001083607.3:c.-59-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354918.2:c.395-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354919.2:c.197-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]

Observations:

Condition(s)

Name:: Gorlin syndrome
Synonyms:: Basal cell nevus syndrome
Identifiers:: MONDO: MONDO:0007187; MedGen: C0004779; Orphanet: 377; OMIM: PS109400

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000196745	CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation	criteria provided, single submitter (Amendola et al. (Genome Res. 2015))	Likely pathogenic (Jun 1, 2014)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV000623015	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 22, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000746634	Undiagnosed Diseases Network, NIH - Undiagnosed Diseases Network (NIH), UDN	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 17, 2016)	paternal	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002032308	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	criteria provided, single submitter (St. Jude Assertion Criteria 2020)	Uncertain significance (Dec 9, 2021)	germline	clinical testing	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, research
White	paternal	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Actionable exomic incidental findings in 6503 participants: challenges of variant classification.

Amendola LM, Dorschner MO, Robertson PD, Salama JS, Hart R, Shirts BH, Murray ML, Tokita MJ, Gallego CJ, Kim DS, Bennett JT, Crosslin DR, Ranchalis J, Jones KL, Rosenthal EA, Jarvik ER, Itsara A, Turner EH, Herman DS, Schleit J, Burt A, Jamal SM, et al.

Genome Res. 2015 Mar;25(3):305-15. doi: 10.1101/gr.183483.114. Epub 2015 Jan 30.

PubMed [citation]

PMID:: 25637381
PMCID:: PMC4352885

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (3)

Details of each submission

From CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation, SCV000196745.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000623015.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This sequence change affects an acceptor splice site in intron 2 of the PTCH1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in the loss of 2 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs368869806, gnomAD 0.0009%). This variant has not been reported in the literature in individuals with PTCH1-related disease. However, it has been observed in several individuals who do not exhibit clinical features consistent with PTCH1-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 162510). Studies have shown that disruption of this splice site results in the activation of a cryptic splice site in exon 3 (Invitae). 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Undiagnosed Diseases Network, NIH - Undiagnosed Diseases Network (NIH), UDN, SCV000746634.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	White	1	not provided	not provided	clinical testing (GTR000553916.1)	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	paternal	yes	not provided	not provided	not provided	(GTR000553916.1)	1	not provided	not provided	not provided

From St. Jude Molecular Pathology, St. Jude Children's Research Hospital, SCV002032308.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The PTCH1 c.395-1G>A intronic change results from a G to A substitution at the -1 position of intron 2 of the PTCH1 gene. This variant is predicted to result in disruption of the native splice site at c.395 and creation of an alternative splice acceptor site at c.401, where use of the alternative splice site would not result in nonsense-mediated decay or aberrant protein, but instead an in-frame deletion of two amino acids. RNA data is consistent with these predictions; half of the reads with the variant use the natural splice site at c.395 and the other half use the alternative splice junction at c.401 which results in the deletion of two amino acids (PVS1_moderate; internal data). Nonsense-mediated decay was not observed (internal data). This variant has a maximum subpopulation frequency of 0.00088% in gnomAD v2.1.1 (PM2_supporting; https://gnomad.broadinstitute.org/variant/8-90955480-C-A?dataset=gnomad_r2_1). This variant has not been reported in the literature in individuals with PTCH1-related disease. However, it has been observed in individuals who do not have a personal or family history of PTCH1-related disease (internal data). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PVS1_moderate, PM2_supporting.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jan 19, 2025

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