DNA sequence analysis of the TINF2 gene demonstrated a sequence change, c.844C>T, in exon 6 that results in an amino acid change, p.Arg282Cys. This sequence change has not been described in population databases (gnomAD, ExAC); however, it has been observed in several individuals with dyskeratosis congenita and aplastic anemia (PMIDs: 19090550, 21199492, 26859482, 18669893, 29742735, 23094712, 30523342). Additionally, several other sequence changes at the same location have been reported to be pathogenic (PMIDs: 18669893, 18252230, 21536674). The p.Arg282Cys change affects a highly conserved amino acid residue located in a domain of the TINF2 protein that is not known to be functional. The p.Arg282Cys substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Functional studies have demonstrated that this sequence change does not impact protein binding in the shelterin complex, however the clinical significance of this finding is unknown at this time (PMID: 22211879). These collective evidences suggest that this sequence change is likely pathogenic.
ClinVar Genomic variation as it relates to human health
NM_001099274.3(TINF2):c.844C>T (p.Arg282Cys)
Germline
Classification
Help
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.
(8)
Help
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
8
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001099274.3(TINF2):c.844C>T (p.Arg282Cys)
Variation ID: 5627 Accession: VCV000005627.21
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 14q12 14: 24240636 (GRCh38) [ NCBI UCSC ] 14: 24709842 (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 4, 2013 Nov 24, 2024 Apr 25, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001099274.3:c.844C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001092744.1:p.Arg282Cys missense NM_001363668.2:c.739C>T NP_001350597.1:p.Arg247Cys missense NM_012461.3:c.844C>T NP_036593.2:p.Arg282Cys missense NC_000014.9:g.24240636G>A NC_000014.8:g.24709842G>A NG_016650.1:g.7039C>T NG_054634.1:g.13220G>A LRG_342:g.7039C>T LRG_342t1:c.844C>T LRG_342p1:p.Arg282Cys LRG_342t2:c.844C>T LRG_342p2:p.Arg282Cys - Protein change
- R282C, R247C
- Other names
-
p.Arg282Cys
- Canonical SPDI
- NC_000014.9:24240635:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe 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) 0.00000
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| TINF2 | - | - |
GRCh38 GRCh38 GRCh37 |
427 | 505 | |
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. |
|---|---|---|---|---|
| Pathogenic (2) |
criteria provided, single submitter
|
Sep 1, 2022 | RCV000005981.6 | |
| not provided (1) |
no classification provided
|
- | RCV000032169.4 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Apr 25, 2024 | RCV000434257.9 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Aug 12, 2021 | RCV001054196.9 |
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
(Nov 19, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV002069638.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
Comment:
DNA sequence analysis of the TINF2 gene demonstrated a sequence change, c.844C>T, in exon 6 that results in an amino acid change, p.Arg282Cys. This sequence … (more)
DNA sequence analysis of the TINF2 gene demonstrated a sequence change, c.844C>T, in exon 6 that results in an amino acid change, p.Arg282Cys. This sequence change has not been described in population databases (gnomAD, ExAC); however, it has been observed in several individuals with dyskeratosis congenita and aplastic anemia (PMIDs: 19090550, 21199492, 26859482, 18669893, 29742735, 23094712, 30523342). Additionally, several other sequence changes at the same location have been reported to be pathogenic (PMIDs: 18669893, 18252230, 21536674). The p.Arg282Cys change affects a highly conserved amino acid residue located in a domain of the TINF2 protein that is not known to be functional. The p.Arg282Cys substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Functional studies have demonstrated that this sequence change does not impact protein binding in the shelterin complex, however the clinical significance of this finding is unknown at this time (PMID: 22211879). These collective evidences suggest that this sequence change is likely pathogenic. (less)
|
|
|
Pathogenic
(Apr 25, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV005414214.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
PP1, PP3, PM1, PM2, PM5, PS2, PS4
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Aug 12, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Dyskeratosis congenita
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001218499.3
First in ClinVar: Apr 15, 2020 Last updated: May 16, 2022 |
|
|
|
Pathogenic
(Sep 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Dyskeratosis congenita, autosomal dominant 3
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002573273.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. It is located in a mutational hot spot and/or well-established functional domain in which established … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. It is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.88; 3Cnet: 0.70). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000005627 ) and different missense changes at the same codon (p.Arg282His, p.Arg282Ser / ClinVar ID: VCV000005625 , VCV000005626 ) have been previously reported as pathogenic/likely pathogenic with strong evidence. Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Reticular hyperpigmentation (present) , Oral mucosa leukoplakia (present) , Gingival overgrowth (present) , Nail dysplasia (present)
|
|
|
Pathogenic
(Dec 30, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Dyskeratosis congenita
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002678402.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.R282C pathogenic mutation (also known as c.844C>T), located in coding exon 6 of the TINF2 gene, results from a C to T substitution at … (more)
The p.R282C pathogenic mutation (also known as c.844C>T), located in coding exon 6 of the TINF2 gene, results from a C to T substitution at nucleotide position 844. The arginine at codon 282 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation was reported in multiple individuals with a clinical diagnosis of dyskeratosis congenita; most cases were reportedly de novo (paternity not confirmed); however, some individuals inherited the mutation from an affected parent (Walne AJ et al. Blood, 2008 Nov;112:3594-600; Du H et al. Medicine (Baltimore), 2018 May;97:e0724). This mutation was also described in two unrelated children with severe aplastic anemia (Du HY et al. Pediatr Blood Cancer, 2009 May;52:687). In addition, the most common TINF2 mutation, p.R282H, occurs at the same codon (Sasa GS et al. Clin. Genet., 2012 May;81:470-8). Based on the supporting evidence, p.R282C is interpreted as a disease-causing mutation. (less)
|
|
|
Pathogenic
(Jan 02, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000514903.6
First in ClinVar: Mar 08, 2017 Last updated: Sep 16, 2024 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26859482, 21199492, 19090550, 29742735, 30523342, 23094712, 22211879, 27033759, 21659346, 18669893, 24168326, 23242325, 34573280, 32054657, 34522616) (less)
|
|
|
Pathogenic
(Nov 01, 2008)
|
no assertion criteria provided
Method: literature only
|
DYSKERATOSIS CONGENITA, AUTOSOMAL DOMINANT 3
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000026163.3
First in ClinVar: Apr 04, 2013 Last updated: Mar 18, 2023 |
Comment on evidence:
In 7 patients with autosomal dominant dyskeratosis congenita-3 (DKCA3; 613990), Walne et al. (2008) identified a heterozygous 844C-T transition in exon 6 of the TINF2 … (more)
In 7 patients with autosomal dominant dyskeratosis congenita-3 (DKCA3; 613990), Walne et al. (2008) identified a heterozygous 844C-T transition in exon 6 of the TINF2 gene, resulting in an arg282-to-cys (R282C) substitution. (less)
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Dyskeratosis congenita, autosomal dominant 1
Affected status: not provided
Allele origin:
unknown
|
GeneReviews
Accession: SCV000055748.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
|
Comment:
Comment:
PP1, PP3, PM1, PM2, PM5, PS2, PS4
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. It is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.88; 3Cnet: 0.70). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000005627 ) and different missense changes at the same codon (p.Arg282His, p.Arg282Ser / ClinVar ID: VCV000005625 , VCV000005626 ) have been previously reported as pathogenic/likely pathogenic with strong evidence. Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
The p.R282C pathogenic mutation (also known as c.844C>T), located in coding exon 6 of the TINF2 gene, results from a C to T substitution at nucleotide position 844. The arginine at codon 282 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation was reported in multiple individuals with a clinical diagnosis of dyskeratosis congenita; most cases were reportedly de novo (paternity not confirmed); however, some individuals inherited the mutation from an affected parent (Walne AJ et al. Blood, 2008 Nov;112:3594-600; Du H et al. Medicine (Baltimore), 2018 May;97:e0724). This mutation was also described in two unrelated children with severe aplastic anemia (Du HY et al. Pediatr Blood Cancer, 2009 May;52:687). In addition, the most common TINF2 mutation, p.R282H, occurs at the same codon (Sasa GS et al. Clin. Genet., 2012 May;81:470-8). Based on the supporting evidence, p.R282C is interpreted as a disease-causing mutation.
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26859482, 21199492, 19090550, 29742735, 30523342, 23094712, 22211879, 27033759, 21659346, 18669893, 24168326, 23242325, 34573280, 32054657, 34522616)
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:
DNA sequence analysis of the TINF2 gene demonstrated a sequence change, c.844C>T, in exon 6 that results in an amino acid change, p.Arg282Cys. This sequence change has not been described in population databases (gnomAD, ExAC); however, it has been observed in several individuals with dyskeratosis congenita and aplastic anemia (PMIDs: 19090550, 21199492, 26859482, 18669893, 29742735, 23094712, 30523342). Additionally, several other sequence changes at the same location have been reported to be pathogenic (PMIDs: 18669893, 18252230, 21536674). The p.Arg282Cys change affects a highly conserved amino acid residue located in a domain of the TINF2 protein that is not known to be functional. The p.Arg282Cys substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Functional studies have demonstrated that this sequence change does not impact protein binding in the shelterin complex, however the clinical significance of this finding is unknown at this time (PMID: 22211879). These collective evidences suggest that this sequence change is likely pathogenic.
Comment:
PP1, PP3, PM1, PM2, PM5, PS2, PS4
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. It is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.88; 3Cnet: 0.70). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000005627 ) and different missense changes at the same codon (p.Arg282His, p.Arg282Ser / ClinVar ID: VCV000005625 , VCV000005626 ) have been previously reported as pathogenic/likely pathogenic with strong evidence. Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
The p.R282C pathogenic mutation (also known as c.844C>T), located in coding exon 6 of the TINF2 gene, results from a C to T substitution at nucleotide position 844. The arginine at codon 282 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation was reported in multiple individuals with a clinical diagnosis of dyskeratosis congenita; most cases were reportedly de novo (paternity not confirmed); however, some individuals inherited the mutation from an affected parent (Walne AJ et al. Blood, 2008 Nov;112:3594-600; Du H et al. Medicine (Baltimore), 2018 May;97:e0724). This mutation was also described in two unrelated children with severe aplastic anemia (Du HY et al. Pediatr Blood Cancer, 2009 May;52:687). In addition, the most common TINF2 mutation, p.R282H, occurs at the same codon (Sasa GS et al. Clin. Genet., 2012 May;81:470-8). Based on the supporting evidence, p.R282C is interpreted as a disease-causing mutation.
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26859482, 21199492, 19090550, 29742735, 30523342, 23094712, 22211879, 27033759, 21659346, 18669893, 24168326, 23242325, 34573280, 32054657, 34522616)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| A de novo TINF2, R282C Mutation in a Case of Dyskeratosis Congenital Founded by Next-Generation Sequencing. | Khakzad M | Iranian biomedical journal | 2023 | PMID: 37070599 |
| Dyskeratosis Congenita and Related Telomere Biology Disorders. | Adam MP | - | 2023 | PMID: 20301779 |
| Severe immunochemotherapy-induced toxicities in a patient with dyskeratosis congenita and literature review. | Geng J | Hematology (Amsterdam, Netherlands) | 2022 | PMID: 36073719 |
| Genetic testing in severe aplastic anemia is required for optimal hematopoietic cell transplant outcomes. | McReynolds LJ | Blood | 2022 | PMID: 35776903 |
| Targeted NGS Yields Plentiful Ultra-Rare Variants in Inborn Errors of Immunity Patients. | Grossi A | Genes | 2021 | PMID: 34573280 |
| Tissue-specific telomere shortening and degenerative changes in a patient with TINF2 mutation and dyskeratosis congenita. | Roake CM | Human pathology (New York) | 2021 | PMID: 34522616 |
| Utility of clinical comprehensive genomic characterization for diagnostic categorization in patients presenting with hypocellular bone marrow failure syndromes. | Blombery P | Haematologica | 2021 | PMID: 32054657 |
| Pathogenic TERT promoter variants in telomere diseases. | Gutierrez-Rodrigues F | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 30523342 |
| A case report of heterozygous TINF2 gene mutation associated with pulmonary fibrosis in a patient with dyskeratosis congenita. | Du H | Medicine | 2018 | PMID: 29742735 |
| Retinal vasculopathy in autosomal dominant dyskeratosis congenita due to TINF2 mutation. | Gleeson M | British journal of haematology | 2012 | PMID: 23094712 |
| Three novel truncating TINF2 mutations causing severe dyskeratosis congenita in early childhood. | Sasa GS | Clinical genetics | 2012 | PMID: 21477109 |
| TINF2 mutations in children with severe aplastic anemia. | Du HY | Pediatric blood & cancer | 2009 | PMID: 19090550 |
| TINF2 mutations result in very short telomeres: analysis of a large cohort of patients with dyskeratosis congenita and related bone marrow failure syndromes. | Walne AJ | Blood | 2008 | PMID: 18669893 |
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Text-mined citations for rs121918545 ...
HelpThese 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 30, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.