VCV000135100.34 - ClinVar

NM_000264.5(PTCH1):c.3583A>T (p.Thr1195Ser)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(16)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Benign/Likely benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000264.5(PTCH1):c.3583A>T (p.Thr1195Ser)

Variation ID: 135100 Accession: VCV000135100.34

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 9q22.32 9: 95449290 (GRCh38) [ NCBI UCSC ] 9: 98211572 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jun 9, 2014	Sep 29, 2024	Feb 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000264.5:c.3583A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000255.2:p.Thr1195Ser	missense
NM_001083603.3:c.3580A>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001077072.1:p.Thr1194Ser	missense
NM_001083602.3:c.3385A>T	NP_001077071.1:p.Thr1129Ser	missense
NM_001083604.3:c.3130A>T	NP_001077073.1:p.Thr1044Ser	missense
NM_001083605.3:c.3130A>T	NP_001077074.1:p.Thr1044Ser	missense
NM_001083606.3:c.3130A>T	NP_001077075.1:p.Thr1044Ser	missense
NM_001083607.3:c.3130A>T	NP_001077076.1:p.Thr1044Ser	missense
NM_001354918.2:c.3427A>T	NP_001341847.1:p.Thr1143Ser	missense
NR_149061.2:n.4322A>T		non-coding transcript variant
NC_000009.12:g.95449290T>A
NC_000009.11:g.98211572T>A
NG_007664.1:g.72676A>T
LRG_515:g.72676A>T
LRG_515t1:c.3583A>T
	Q13635:p.Thr1195Ser

... more HGVS ... less HGVS

Protein change

T1129S, T1195S, T1143S, T1194S, T1044S

Other names

p.T1195S:ACA>TCA

Canonical SPDI

NC_000009.12:95449289:T:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.07847 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.05093

Exome Aggregation Consortium (ExAC) 0.05456

1000 Genomes Project 30x 0.07730

1000 Genomes Project 0.07847

The Genome Aggregation Database (gnomAD) 0.04656

The Genome Aggregation Database (gnomAD), exomes 0.03401

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.04173

Links

dbSNP: rs2236405 ClinGen: CA161704 UniProtKB: Q13635#VAR_020440 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
PTCH1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	4024	5237

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not specified	Benign (5)	criteria provided, multiple submitters, no conflicts	Mar 2, 2016	RCV000121893.21
not provided	Benign/Likely benign (5)	criteria provided, multiple submitters, no conflicts	Sep 22, 2023	RCV000127647.23
Gorlin syndrome	Benign/Likely benign (3)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV000266478.22
Holoprosencephaly 7	Likely benign (1)	criteria provided, single submitter	Apr 27, 2017	RCV000361116.13
Hereditary cancer-predisposing syndrome	Benign (2)	criteria provided, multiple submitters, no conflicts	Dec 9, 2019	RCV000492383.11

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Benign (Aug 27, 2013)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	GeneDx Accession: SCV000171226.2 First in ClinVar: Jun 23, 2014 Last updated: Jun 23, 2014	Comment: The variant is found in PTCH panel(s).
Benign (Mar 02, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000303353.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Likely Benign (Jul 22, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000511433.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Comment: Converted during submission to Likely benign.
Benign (May 24, 2016)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000696379.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (2) PubMed: 12925203‚ 15712338 Comment: Variant summary: The PTCH1 c.3583A>T (p.Thr1195Ser) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant … (more) Variant summary: The PTCH1 c.3583A>T (p.Thr1195Ser) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 1271/23496 control chromosomes (51 homozygotes) at a frequency of 0.0540943, which is approximately 3157 times the estimated maximal expected allele frequency of a pathogenic PTCH1 variant (0.0000171), suggesting this variant is likely a benign polymorphism. This variant has been reported in NBCCS patients. One patient also carried a potentially pathogenic variant c.3499G>A (p.G1167R), further supporting the benign classification. In addition, multiple clinical diagnostic laboratories classified this variant as benign. Taken together, this variant is classified as benign. (less)
Benign (Mar 13, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000227879.5 First in ClinVar: Jun 28, 2015 Last updated: Oct 02, 2016	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PTCH1 Number of individuals with the variant: 1 Sex: mixed
Benign (Dec 09, 2019)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002526896.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Benign (Feb 01, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Gorlin syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001000481.6 First in ClinVar: Dec 17, 2019 Last updated: Feb 20, 2024
Benign (Sep 22, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001477610.5 First in ClinVar: Jan 26, 2021 Last updated: Feb 20, 2024
Likely benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Basal cell nevus syndrome 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000481271.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Likely benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Holoprosencephaly 7 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000481270.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Benign (Jul 07, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Basal cell nevus syndrome 1 Affected status: yes Allele origin: germline	KCCC/NGS Laboratory, Kuwait Cancer Control Center Accession: SCV004017131.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023
Benign (Dec 03, 2014)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000581023.6 First in ClinVar: Jul 01, 2017 Last updated: May 01, 2024	Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005222444.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001798284.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001929857.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
not provided (Sep 19, 2013)	no classification provided Method: reference population	AllHighlyPenetrant Affected status: unknown Allele origin: germline	ITMI Accession: SCV000086096.1 First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014 Comment: Please see associated publication for description of ethnicities	Publications: PubMed (1) PubMed: 24728327 Observation 1: Ethnicity/Population group: Whole_cohort Observation 2: Ethnicity/Population group: African Observation 3: Ethnicity/Population group: African_European Observation 4: Ethnicity/Population group: Central_Asian Observation 5: Ethnicity/Population group: East_Asian Observation 6: Ethnicity/Population group: European Observation 7: Ethnicity/Population group: Hispanic
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Comment:

Variant summary: The PTCH1 c.3583A>T (p.Thr1195Ser) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 1271/23496 control chromosomes (51 homozygotes) at a frequency of 0.0540943, which is approximately 3157 times the estimated maximal expected allele frequency of a pathogenic PTCH1 variant (0.0000171), suggesting this variant is likely a benign polymorphism. This variant has been reported in NBCCS patients. One patient also carried a potentially pathogenic variant c.3499G>A (p.G1167R), further supporting the benign classification. In addition, multiple clinical diagnostic laboratories classified this variant as benign. Taken together, this variant is classified as benign.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Molecular characterization of Italian nevoid basal cell carcinoma syndrome patients.	Pastorino L	Human mutation	2005	PMID: 15712338
Spectrum of PTCH1 mutations in French patients with Gorlin syndrome.	Boutet N	The Journal of investigative dermatology	2003	PMID: 12925203
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PTCH1	-	-	-	-

Text-mined citations for rs2236405 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000264.5(PTCH1):c.3583A>T (p.Thr1195Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs2236405 ...