VCV002501709.3 - ClinVar

NM_015450.3(POT1):c.776T>C (p.Leu259Ser)

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.

(1)

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.

Pathogenic

no assertion criteria provided

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_015450.3(POT1):c.776T>C (p.Leu259Ser)

Variation ID: 2501709 Accession: VCV002501709.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q31.33 7: 124853065 (GRCh38) [ NCBI UCSC ] 7: 124493119 (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	May 13, 2023	Sep 30, 2023	Sep 26, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_015450.3:c.776T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_056265.2:p.Leu259Ser	missense
NM_001042594.2:c.383T>C	NP_001036059.1:p.Leu128Ser	missense
NR_003102.2:n.1219T>C		non-coding transcript variant
NR_003103.2:n.1219T>C		non-coding transcript variant
NR_003104.2:n.1219T>C		non-coding transcript variant
NC_000007.14:g.124853065A>G
NC_000007.13:g.124493119A>G
NG_029232.1:g.81919T>C

... more HGVS ... less HGVS

Protein change

L259S, L128S

Other names

Canonical SPDI

NC_000007.14:124853064:A:G

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.

Links

OMIM: 606478.0012 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.
POT1		-	-	GRCh38 GRCh37	2081	2110

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.
Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 8	Pathogenic (1)	no assertion criteria provided	Sep 26, 2023	RCV003227580.2

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.
Pathogenic (Sep 26, 2023)	no assertion criteria provided Method: literature only	PULMONARY FIBROSIS AND/OR BONE MARROW FAILURE SYNDROME, TELOMERE-RELATED, 8 (1 family) Affected status: not provided Allele origin: germline	OMIM Accession: SCV003924089.2 First in ClinVar: May 13, 2023 Last updated: Sep 30, 2023	Publications: PubMed (1) PubMed: 35420632 Comment on evidence: In 4 affected members of a family with telomere-related pulmonary fibrosis and/or bone marrow failure syndrome-8 (PFBMFT8; 620367), Kelich et al. (2022) identified a heterozygous … (more) In 4 affected members of a family with telomere-related pulmonary fibrosis and/or bone marrow failure syndrome-8 (PFBMFT8; 620367), Kelich et al. (2022) identified a heterozygous c.776T-C transition (c.776T-C, NM_015450.2) in the POT1 gene, resulting in a leu259-to-ser (L259S) substitution at a conserved residue. The mutation, which was found by next-generation panel sequencing, segregated with the disorder in the family and was not present in the gnomAD database. In vitro functional expression studies showed that the mutant protein had decreased DNA binding affinity compared to wildtype, although it was able to interact with TPP1 (ACD; 609377) and localize to telomeres. Nuclear localization was reduced, suggesting that less POT1 is bound to DNA. Although the patients were noted to have short telomeres, the mutant protein did not negatively affect telomerase extension activity in vitro. Patient fibroblasts harboring the mutation had shortened lagging strands during synthesis, an increase in the telomeric overhang signal, and sister telomere loss during metaphase. The L259S mutation led to an increase in telomere dysfunction-induced foci in patient cells, suggesting a defect in telomere capping that could lead to shortened telomeres. Finally, the L259S mutation induced premature cellular senescence in patient cells, likely a consequence of telomere-induced DNA damage resulting from the mutation. Of note, HEK293 cells expressing the mutation in vitro developed longer telomeres compared to wildtype, suggesting that mutant POT1 is defective in limiting telomere elongation in cells. (less)

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.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Telomere dysfunction implicates POT1 in patients with idiopathic pulmonary fibrosis.	Kelich J	The Journal of experimental medicine	2022	PMID: 35420632

Text-mined citations for this variant ...

Record last updated Dec 02, 2023

ClinVar Genomic variation as it relates to human health

NM_015450.3(POT1):c.776T>C (p.Leu259Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...