POT1

protein-coding

protection of telomeres 1, the group of Shelterin complex

Gene summary

This gene is a member of the telombin family and encodes a nuclear protein involved in telomere maintenance. Specifically, this protein functions as a member of a multi-protein complex that binds to the TTAGGG repeats of telomeres, regulating telomere length and protecting chromosome ends from illegitimate recombination, catastrophic chromosome instability, and abnormal chromosome segregation. Increased transcriptional expression of this gene is associated with stomach carcinogenesis and its progression. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jul 2008]

MANE transcript

NM_015450.3

Inheritance

AD, AR

ClinVar variants

P:258U:1216B:611

Top phenotype

Tumor predisposition syndrome 3; Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 8; Cerebroretinal microangiopathy with calcifications and cysts 3

gnomAD constraint

pLI —, LoF o/e 0.18

Max pathogenic AF

—

Genomic locus

chr7:124,822,386-124,929,983

External References & Databases

Ensembl (ENSG00000128513)

Transcript & Mutation Effects

hg38 • Region Span ~107.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 8STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0957263

Submitter: Labcorp Genetics (formerly Invitae)

cerebroretinal microangiopathy with calcifications and cysts 3LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0957264

Submitter: Ambry Genetics

glioma susceptibility 9LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0014695

Submitter: Ambry Genetics

tumor predisposition syndrome 3MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0014368

Submitter: Ambry Genetics

thyroid gland carcinomaLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0015075

Submitter: Ambry Genetics

pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 8LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0957263

Submitter: Ambry Genetics

cerebroretinal microangiopathy with calcifications and cysts 3LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0957264

Submitter: G2P

tumor predisposition syndrome 3DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014368

Submitter: ClinGen

POT1 was first reported in relation to autosomal dominant familial melanoma in 2014 (Robles-Espinoza et al., PMID: 24686849). POT1 was also reported in relation to Coats plus (Takai et al., PMID: 27013236) and pulmonary fibrosis (Kelich et al., PMID: 35420632). Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found a difference in inheritance pattern and phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities: cerebroretinal microangiopathy with calcifications and cysts 3 (OMIM:620368), pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 8 (OMIM:620367), and tumor predisposition syndrome 3 (OMIM:615848). The split curations for autosomal recessive cerebroretinal microangiopathy with calcifications and cysts and autosomal dominant pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, have been curated separately. In total, 6 missense variants, 2 splicing variants, and 4 frameshift variants that have been reported in 21 probands in 7 publications (PMIDs: 38540414, 34769003, 32907878, 24686849, 38839987, 33050356, and 39156708) are included in this curation for POT1-related tumor predisposition syndrome (OMIM:615848). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss of function. This gene-disease relationship is also supported by a non-human model organism (PMID: 27869160) in which mice receiving a transplant of cells with POT1 variants develop DNA damage foci and dysplastic hematopoietic cells. In summary, there is definitive evidence supporting the relationship between POT1 and autosomal dominant POT1-related tumor predisposition syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Children, Adolescent and Young Adult Cancer Predisposition GCEP on the meeting date September 9, 2025 (SOP Version 11).

Clinical Genomic Database (CGD)

Tumor predisposition syndrome 3; Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 8; Cerebroretinal microangiopathy with calcifications and cysts 3AD/AR

Manifestation: Allergy/Immunology/Infectious; Dermatologic; Gastrointestinal; Hematologic; Musculoskeletal; Oncologic; Ophthalmologic; Pulmonary

Intervention: Allergy/Immunology/Infectious; Gastrointestinal; Hematologic; Oncologic; Pulmonary

Rationale: For Tumor predisposition syndrome 3, awareness of risk of glioma and melanoma (as well as other malignancies) may allow surveillance and early disease detection and management; Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related can involve hepatic manifestations, and awareness may allow early diagnosis and medical and surgical management; Surveillance and prompt treatment of findings related to bone marrow failure may reduce morbidity; For treatment related to pulmonary fibrosis, early recognition may allow prompt medical management; Cerebroretinal microangiopathy with calcifications and cysts can involve gastrointestinal ectasias wit hrisk of bleeding, and awareness may beneft medical management

Comments: Susceptibility to cancer types other than melanoma and glioma has been suggested in the reported families with variants related to susceptibility to neoplasms

Refs: 24686846; 24686849; 25482530; 27013236; 35420632; 37140166

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to POT1 variants in ClinVar

21 Conditions Cataloged

Tumor predisposition syndrome 3Total: 1867

Hereditary cancer-predisposing syndromeTotal: 1599

not providedTotal: 336

not specifiedTotal: 166

POT1-related disorderTotal: 69

Cerebroretinal microangiopathy with calcifications and cysts 3Total: 30

Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 8Total: 30

Long telomere syndromeTotal: 24

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015450.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous		1 clinvar	14 clinvar	481 clinvar	3 clinvar	499
missense	3 clinvar	22 clinvar	1167 clinvar	125 clinvar	2 clinvar	1319
nonsense	52 clinvar	12 clinvar	3 clinvar			67
start loss	3 clinvar	2 clinvar	1 clinvar			6
frameshift	87 clinvar	20 clinvar	10 clinvar			117
splice donor/acceptor (+/-2bp)	2 clinvar	54 clinvar	21 clinvar			77
Total	147	111	1216	606	5	2085

Highest pathogenic variant AF is 0.000062770734

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 58 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015450.3	RefSeq	NP_056265.2	15	MANE Select
ENST00000357628.8	Ensembl	ENSP00000350249.3	15	MANE Select
NM_001042594.2	RefSeq	NP_001036059.1	12	Standard
ENST00000393329.5	Ensembl	ENSP00000377002.1	12	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Packaging Of Telomere Ends
Telomere Maintenance
Chromosome Maintenance
Cell Cycle
Regulation of Telomerase

Biological Process

telomere maintenance via telomerase
telomere capping
telomere assembly
regulation of telomere maintenance via telomerase
negative regulation of telomere maintenance via telomerase

Molecular Function

protein binding
telomerase inhibitor activity
DEAD/H-box RNA helicase binding
telomeric DNA binding
single-stranded telomeric DNA binding

Cellular Component

chromosome, telomeric region
nuclear telomere cap complex
nuclear chromosome, telomeric region
nucleus
nucleoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000357628
Coding exons: 15
Length: 107598
Individuals with no LoFs: 125705
Homozygous LoFs: 0
Heterozygous LoFs: 39
Defined: 125744
p: 0.000155

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.92	226	323	0.699	0.0000158	4128
Missense (PolyPhen)		47	79.085	0.5943		955
Synonymous	-0.755	129	119	1.09	0.00000631	1197
Loss of Function	4.33	6	32.7	0.183	0.00000147	439

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00026	0.00025	rare
South Asian	0.00010	0.000098	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of the telomerase ribonucleoprotein (RNP) complex that is essential for the replication of chromosome termini. Is a component of the double-stranded telomeric DNA- binding TRF1 complex which is involved in the regulation of telomere length by cis-inhibition of telomerase. Also acts as a single-stranded telomeric DNA-binding protein and thus may act as a downstream effector of the TRF1 complex and may transduce information about telomere maintenance and/or length to the telomere terminus. Component of the shelterin complex (telosome) that is involved in the regulation of telomere length and protection. Shelterin associates with arrays of double-stranded TTAGGG repeats added by telomerase and protects chromosome ends; without its protective activity, telomeres are no longer hidden from the DNA damage surveillance and chromosome ends are inappropriately processed by DNA repair pathways. Binds to two or more telomeric single-stranded 5'-TTAGGG-3' repeats (G-strand) and with high specificity to a minimal telomeric single-stranded 5'- TAGGGTTAG-3' sequence. Binds telomeric single-stranded sequences internally or at proximity of a 3'-end. Its activity is TERT dependent but it does not increase TERT activity by itself. In contrast, the ACD-POT1 heterodimer enhances telomere elongation by increasing telomerase processivity. {ECO:0000269|PubMed:12768206, ECO:0000269|PubMed:12781132, ECO:0000269|PubMed:16166375, ECO:0000269|PubMed:17237768, ECO:0000269|PubMed:20231318}.;
Disease: DISEASE: Glioma 9 (GLM9) [MIM:616568]: Gliomas are benign or malignant central nervous system neoplasms derived from glial cells. They comprise astrocytomas and glioblastoma multiforme that are derived from astrocytes, oligodendrogliomas derived from oligodendrocytes and ependymomas derived from ependymocytes. {ECO:0000269|PubMed:25482530}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.162

Intolerance Scores

LoFtool: 0.832
RVIS EVS: 0.04
RVIS percentile EVS: 57.15

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): K
Indispensability pred.: N
Indispensability score: 0.309

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium