VCV000008224.46 - ClinVar

NM_000264.5(PTCH1):c.3155C>T (p.Thr1052Met)

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.

(18)

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.

Conflicting classifications of pathogenicity
Uncertain significance(2); Benign(3); Likely benign(4)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000264.5(PTCH1):c.3155C>T (p.Thr1052Met)

Variation ID: 8224 Accession: VCV000008224.46

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 9q22.32 9: 95458026 (GRCh38) [ NCBI UCSC ] 9: 98220308 (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	Apr 12, 2013	Oct 20, 2024	Jan 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000264.5:c.3155C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000255.2:p.Thr1052Met	missense
NM_001083603.3:c.3152C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001077072.1:p.Thr1051Met	missense
NM_001083602.3:c.2957C>T	NP_001077071.1:p.Thr986Met	missense
NM_001083604.3:c.2702C>T	NP_001077073.1:p.Thr901Met	missense
NM_001083605.3:c.2702C>T	NP_001077074.1:p.Thr901Met	missense
NM_001083606.3:c.2702C>T	NP_001077075.1:p.Thr901Met	missense
NM_001083607.3:c.2702C>T	NP_001077076.1:p.Thr901Met	missense
NM_001354918.2:c.2999C>T	NP_001341847.1:p.Thr1000Met	missense
NR_149061.2:n.3894C>T		non-coding transcript variant
NC_000009.12:g.95458026G>A
NC_000009.11:g.98220308G>A
NG_007664.1:g.63940C>T
LRG_515:g.63940C>T
LRG_515t1:c.3155C>T
LRG_515t2:c.2957C>T
	Q13635:p.Thr1052Met

... more HGVS ... less HGVS

Protein change

T1052M, T986M, T1051M, T901M, T1000M

Other names

Canonical SPDI

NC_000009.12:95458025:G: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.

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

Trans-Omics for Precision Medicine (TOPMed) 0.00058

Exome Aggregation Consortium (ExAC) 0.00062

The Genome Aggregation Database (gnomAD), exomes 0.00065

The Genome Aggregation Database (gnomAD) 0.00066

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00115

Links

ClinGen: CA161680 UniProtKB: Q13635#VAR_032958 OMIM: 601309.0014 dbSNP: rs138911275 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	4020	5232

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.
Holoprosencephaly 7	Uncertain significance (2)	criteria provided, single submitter	Apr 27, 2017	RCV000008707.12
not provided	Benign/Likely benign (9)	criteria provided, multiple submitters, no conflicts	Sep 1, 2023	RCV000034570.28
Holoprosencephaly sequence	Likely benign (1)	no assertion criteria provided	Jun 1, 2014	RCV000148761.6
not specified	Uncertain significance (2)	criteria provided, single submitter	Aug 15, 2023	RCV000121888.7
Gorlin syndrome	Benign (1)	criteria provided, single submitter	Jan 31, 2024	RCV001081022.13
Hereditary cancer-predisposing syndrome	Benign/Likely benign (2)	criteria provided, multiple submitters, no conflicts	Dec 4, 2020	RCV000574977.7
PTCH1-related disorder	Likely benign (1)	no assertion criteria provided	Jan 17, 2020	RCV004547468.2

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.
Uncertain significance (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: SCV001331103.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (2) PubMed: 8302318‚ 11941477 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Benign (Apr 04, 2021)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV002046845.1 First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022	Publications: PubMed (9) PubMed: 27153395‚ 26893459‚ 26489027‚ 25637381‚ 24055113‚ 22820256‚ 22703879‚ 17001668‚ 11941477
Benign (Dec 04, 2020)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002526878.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Likely benign (Jun 09, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000514302.6 First in ClinVar: Mar 08, 2017 Last updated: Mar 04, 2023	Comment: This variant is associated with the following publications: (PMID: 26893459, 26353884, 27498913, 22885699, 11941477, 24728327, 26875496, 22703879, 21188540, 24055113, 25637381, 22820256, 23718828, 17001668, 20635334, 24686850, … (more) This variant is associated with the following publications: (PMID: 26893459, 26353884, 27498913, 22885699, 11941477, 24728327, 26875496, 22703879, 21188540, 24055113, 25637381, 22820256, 23718828, 17001668, 20635334, 24686850, 24211491, 26489027, 26986070, 27153395, 27930734, 29575684, 33209614) (less)
Likely benign (Nov 03, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV002011173.3 First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023
Uncertain significance (Aug 15, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV004027554.1 First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023
Benign (Jan 31, 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: SCV000153864.13 First in ClinVar: Jun 03, 2014 Last updated: Feb 20, 2024
Likely benign (Sep 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV003917674.13 First in ClinVar: Apr 23, 2023 Last updated: Oct 20, 2024	Comment: PTCH1: BS1 Number of individuals with the variant: 3
Likely benign (Sep 26, 2018)	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: SCV000674462.5 First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024	Publications: PubMed (10) PubMed: 11941477‚ 21188540‚ 22703879‚ 22820256‚ 24055113‚ 24728327‚ 25637381‚ 26489027‚ 26893459‚ 27153395 Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely 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)
variant of unknown significance (Jul 13, 2012)	no assertion criteria provided Method: research	not provided Affected status: no Allele origin: germline	Biesecker Lab/Clinical Genomics Section, National Institutes of Health Study: ClinSeq Accession: SCV000043451.1 First in ClinVar: Apr 12, 2013 Last updated: Apr 12, 2013	Publications: PubMed (1) PubMed: 22703879 Comment: Converted during submission to Uncertain significance. Number of individuals with the variant: 3 Comment on evidence: The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for … (more) The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for details. (less)
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided 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: SCV001931167.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Pathogenic (Dec 01, 2006)	no assertion criteria provided Method: literature only	HOLOPROSENCEPHALY 7 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000028916.4 First in ClinVar: Apr 04, 2013 Last updated: Apr 30, 2023	Publications: PubMed (2) PubMed: 11941477‚ 17001668 Comment on evidence: In a male with alobar holoprosencephaly and hypotelorism and in his brother with hypotelorism and developmental delay (HPE7; 610828), Ming et al. (2002) found a … (more) In a male with alobar holoprosencephaly and hypotelorism and in his brother with hypotelorism and developmental delay (HPE7; 610828), Ming et al. (2002) found a heterozygous 3143C-T transition in the PTCH gene resulting in a thr1052-to-met (T1052M) amino acid substitution in an intracellular loop of the PTCH protein. Their clinically normal father also carried the mutation; their sister and mother, both of whom had normal cognitive development, did not carry the mutation. Ribeiro et al. (2006) described the T1052M mutation in a Brazilian girl with holoprosencephaly-like facial features but normal MRI. (less)
Likely benign (Jan 17, 2020)	no assertion criteria provided Method: clinical testing	PTCH1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004759160.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Likely benign (Jun 01, 2014)	no assertion criteria provided Method: research	Holoprosencephaly (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	CSER _CC_NCGL, University of Washington Study: ESP 6500 variant annotation Accession: SCV000190498.1 First in ClinVar: Dec 06, 2014 Last updated: Dec 06, 2014 Comment: Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001798067.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV001807240.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001739541.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
not provided (Sep 19, 2013)	no classification provided Method: reference population	AllHighlyPenetrant Affected status: unknown Allele origin: germline	ITMI Accession: SCV000086091.1 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:

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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

This variant is associated with the following publications: (PMID: 26893459, 26353884, 27498913, 22885699, 11941477, 24728327, 26875496, 22703879, 21188540, 24055113, 25637381, 22820256, 23718828, 17001668, 20635334, 24686850, 24211491, 26489027, 26986070, 27153395, 27930734, 29575684, 33209614)

Comment:

This alteration is classified as likely 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
Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer.	Maxwell KN	American journal of human genetics	2016	PMID: 27153395
Targeted resequencing identifies PTCH1 as a major contributor to ocular developmental anomalies and extends the SOX2 regulatory network.	Chassaing N	Genome research	2016	PMID: 26893459
Prioritization and burden analysis of rare variants in 208 candidate genes suggest they do not play a major role in CAKUT.	Nicolaou N	Kidney international	2016	PMID: 26489027
Actionable exomic incidental findings in 6503 participants: challenges of variant classification.	Amendola LM	Genome research	2015	PMID: 25637381
Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing.	Bodian DL	PloS one	2014	PMID: 24728327
Actionable, pathogenic incidental findings in 1,000 participants' exomes.	Dorschner MO	American journal of human genetics	2013	PMID: 24055113
Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations.	Pugh TJ	Nature	2012	PMID: 22820256
Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes.	Johnston JJ	American journal of human genetics	2012	PMID: 22703879
Heterogeneity of familial medulloblastoma and contribution of germline PTCH1 and SUFU mutations to sporadic medulloblastoma.	Slade I	Familial cancer	2011	PMID: 21188540
PTCH mutations in four Brazilian patients with holoprosencephaly and in one with holoprosencephaly-like features and normal MRI.	Ribeiro LA	American journal of medical genetics. Part A	2006	PMID: 17001668
Mutations in PATCHED-1, the receptor for SONIC HEDGEHOG, are associated with holoprosencephaly.	Ming JE	Human genetics	2002	PMID: 11941477
Mutations of the P gene in oculocutaneous albinism, ocular albinism, and Prader-Willi syndrome plus albinism.	Lee ST	The New England journal of medicine	1994	PMID: 8302318
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Text-mined citations for rs138911275 ...

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 10, 2024

ClinVar Genomic variation as it relates to human health

NM_000264.5(PTCH1):c.3155C>T (p.Thr1052Met)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs138911275 ...