This missense change has been observed in individuals with dyskeratosis congenita (PMID: 18252230, 18669893). Experimental studies have shown that this missense change affects TINF2 function (PMID: 21477109, 21536674, 29581185). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 5625). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 282 of the TINF2 protein (p.Arg282His). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg282 amino acid residue in TINF2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18669893, 19090550, 21199492, 23094712, 26859482, 29742735). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing.
ClinVar Genomic variation as it relates to human health
NM_001099274.3(TINF2):c.845G>A (p.Arg282His)
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.
(9)
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
9
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.845G>A (p.Arg282His)
Variation ID: 5625 Accession: VCV000005625.22
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 14q12 14: 24240635 (GRCh38) [ NCBI UCSC ] 14: 24709841 (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 May 1, 2024 May 11, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001099274.3:c.845G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001092744.1:p.Arg282His missense NM_001363668.2:c.740G>A NP_001350597.1:p.Arg247His missense NM_012461.3:c.845G>A NP_036593.2:p.Arg282His missense NC_000014.9:g.24240635C>T NC_000014.8:g.24709841C>T NG_016650.1:g.7040G>A NG_054634.1:g.13219C>T LRG_342:g.7040G>A LRG_342t1:c.845G>A LRG_342p1:p.Arg282His LRG_342t2:c.845G>A LRG_342p2:p.Arg282His Q9BSI4:p.Arg282His - Protein change
- R282H, R247H
- Other names
- -
- Canonical SPDI
- NC_000014.9:24240634:C:T
-
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.
- -
- 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 (4) |
criteria provided, multiple submitters, no conflicts
|
Nov 23, 2017 | RCV000005978.14 | |
| Pathogenic (1) |
no assertion criteria provided
|
May 1, 2012 | RCV000005979.4 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 30, 2021 | RCV001509450.7 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
May 11, 2023 | RCV001382425.8 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 2, 2022 | RCV002490324.1 |
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
(Jul 07, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Dyskeratosis congenita, autosomal dominant 3
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000249157.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
|
|
|
Pathogenic
(Nov 23, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Dyskeratosis congenita, autosomal dominant 3
Affected status: yes
Allele origin:
de novo
|
Degerman lab, Umeå University
Accession: SCV000611706.1
First in ClinVar: Aug 20, 2018 Last updated: Aug 20, 2018 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Apr 02, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Dyskeratosis congenita, autosomal dominant 1
Revesz syndrome Dyskeratosis congenita, autosomal dominant 3
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002796913.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(May 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Dyskeratosis congenita
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001581189.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This missense change has been observed in individuals with dyskeratosis congenita (PMID: 18252230, 18669893). Experimental studies have shown that this missense change affects TINF2 function … (more)
This missense change has been observed in individuals with dyskeratosis congenita (PMID: 18252230, 18669893). Experimental studies have shown that this missense change affects TINF2 function (PMID: 21477109, 21536674, 29581185). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 5625). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 282 of the TINF2 protein (p.Arg282His). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg282 amino acid residue in TINF2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18669893, 19090550, 21199492, 23094712, 26859482, 29742735). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. (less)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Dyskeratosis congenita, autosomal dominant 3
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Lifecell International Pvt. Ltd
Accession: SCV003842251.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Comment:
A Heterozygous Missense variant c.845G>A in Exon 6 of the TINF2 gene that results in the amino acid substitution p.Arg282His was identified. The observed variant … (more)
A Heterozygous Missense variant c.845G>A in Exon 6 of the TINF2 gene that results in the amino acid substitution p.Arg282His was identified. The observed variant has a minor allelefrequency of 0.000% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individualtools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for anindividual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. The variant has been reported to ClinVar as Pathogenic with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 5625 as of 2022-12-31). The p.R282H pathogenic mutation (also known as c.845G>A), located in coding exon 6 of the TINF2 gene, results from a G to A substitution at nucleotide position 845. The arginine at codon 282 is replaced by histidine, an amino acid with highly similar properties.This pathogenic mutation was first reported in three unrelated individuals with dyskeratosis congenita (DC) and very short telomeres (Savage, Sharon A et al., 2008; Walne, Amanda J et al., 2008; Vulliamy, T et al., 2012). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. (less)
Ethnicity/Population group: Asian
Geographic origin: India
|
|
|
Pathogenic
(Mar 30, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001716177.2
First in ClinVar: Jun 15, 2021 Last updated: Jun 03, 2023 |
Comment:
PS3, PS4_moderate, PM1, PM2_supporting, PP3
|
|
|
Pathogenic
(Dec 20, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Dyskeratosis congenita
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002676023.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.R282H pathogenic mutation (also known as c.845G>A), located in coding exon 6 of the TINF2 gene, results from a G to A substitution at … (more)
The p.R282H pathogenic mutation (also known as c.845G>A), located in coding exon 6 of the TINF2 gene, results from a G to A substitution at nucleotide position 845. The arginine at codon 282 is replaced by histidine, an amino acid with highly similar properties.This pathogenic mutation was first reported in three unrelated individuals with dyskeratosis congenita (DC) and very short telomeres (Savage SA et al. Am. J. Hum. Genet., 2008 Feb;82:501-9). Another study identified this mutation in an additional 14 individuals with DC and short telomeres; parental testing determined the majority of the identified mutations were de novo occurrences. In this cohort, individuals with this pathogenic mutation had clinically severe presentations, including individuals with Revesz syndrome and Hoyeraal-Hreidarsson syndrome (Walne AJ et al. Blood, 2008 Nov;112:3594-600). An in vitro functional study found this pathogenic mutation lead to telomere shortening, but did not affect telomerase activity, total levels of TERC, ,or cell proliferation; the authors propose telomere shortening may occur due to a defect in telomerase trafficking (Yang D et al. J. Biol. Chem., 2011 Jul;286:23022-30). Based on the supporting evidence, p.R282H is interpreted as a disease-causing mutation. (less)
|
|
|
Pathogenic
(May 01, 2012)
|
no assertion criteria provided
Method: literature only
|
REVESZ SYNDROME
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000026161.2
First in ClinVar: Apr 04, 2013 Last updated: Mar 18, 2023 |
Comment on evidence:
In 3 individuals with autosomal dominant dyskeratosis congenita-3 (DKCA3; 613990), Savage et al. (2008) identified heterozygosity for a G-to-A transition in exon 6 of the … (more)
In 3 individuals with autosomal dominant dyskeratosis congenita-3 (DKCA3; 613990), Savage et al. (2008) identified heterozygosity for a G-to-A transition in exon 6 of the TINF2 gene (Ex6+241G-A) that resulted in an arg282-to-his (R282H) amino acid substitution. Two of these patients had the 'DKC triad' of abnormal nails, reticular pigmentation, and oral leukoplakia, with other features; 1 of these patients had Revesz syndrome (268130). One patient without the DKC triad had dystrophic nails and IgA deficiency. All 3 patients had telomere lengths below the first percentile for age. Tsangaris et al. (2008) identified a de novo heterozygous R282H mutation in an 18-month-old girl with DKC who presented with pancytopenia and ataxia. Brain imaging showed cerebellar hypoplasia. She later developed a small area of leukoplakia, but had no nail dystrophy or skin hyperpigmentation. Laboratory studies showed shortened telomeres and decreased telomerase activity (92.5% reduction compared to control values). The authors noted that the phenotype was consistent with the ataxia-pancytopenia syndrome (159550), which may be part of the phenotypic spectrum of DKC. Yang et al. (2011) showed that the R282H mutation caused defective targeting of telomerase to telomere ends. By in vitro functional expression studies in HEK293 cells, Sasa et al. (2012) demonstrated that the R282H mutant protein retained substantial ability to interact with TERF1 (600951). Vulliamy et al. (2012) identified a heterozygous R282H mutation in 7 unrelated patients with DKC. Two had a severe form of the disorder, with additional features including growth retardation, retinopathy, ataxia, developmental delay, and cerebellar hypoplasia, consistent with a clinical diagnosis of Hoyeraal-Hreidarsson syndrome. Three patients had classic DKC, with bone marrow failure and skin and nail involvement; 2 had leukoplakia. The last 2 patients had bone marrow failure with variable features overlapping DKC, mainly nail dystrophy; 1 had intracranial calcifications. Telomere length was only available from 4 of these patients, but all showed significantly shortened telomeres. The findings indicated that TINF2 mutations can be associated with a broad spectrum of phenotypes. (less)
|
|
|
Pathogenic
(May 01, 2012)
|
no assertion criteria provided
Method: literature only
|
DYSKERATOSIS CONGENITA, AUTOSOMAL DOMINANT 3
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000026160.3
First in ClinVar: Apr 04, 2013 Last updated: Mar 18, 2023 |
Comment on evidence:
In 3 individuals with autosomal dominant dyskeratosis congenita-3 (DKCA3; 613990), Savage et al. (2008) identified heterozygosity for a G-to-A transition in exon 6 of the … (more)
In 3 individuals with autosomal dominant dyskeratosis congenita-3 (DKCA3; 613990), Savage et al. (2008) identified heterozygosity for a G-to-A transition in exon 6 of the TINF2 gene (Ex6+241G-A) that resulted in an arg282-to-his (R282H) amino acid substitution. Two of these patients had the 'DKC triad' of abnormal nails, reticular pigmentation, and oral leukoplakia, with other features; 1 of these patients had Revesz syndrome (268130). One patient without the DKC triad had dystrophic nails and IgA deficiency. All 3 patients had telomere lengths below the first percentile for age. Tsangaris et al. (2008) identified a de novo heterozygous R282H mutation in an 18-month-old girl with DKC who presented with pancytopenia and ataxia. Brain imaging showed cerebellar hypoplasia. She later developed a small area of leukoplakia, but had no nail dystrophy or skin hyperpigmentation. Laboratory studies showed shortened telomeres and decreased telomerase activity (92.5% reduction compared to control values). The authors noted that the phenotype was consistent with the ataxia-pancytopenia syndrome (159550), which may be part of the phenotypic spectrum of DKC. Yang et al. (2011) showed that the R282H mutation caused defective targeting of telomerase to telomere ends. By in vitro functional expression studies in HEK293 cells, Sasa et al. (2012) demonstrated that the R282H mutant protein retained substantial ability to interact with TERF1 (600951). Vulliamy et al. (2012) identified a heterozygous R282H mutation in 7 unrelated patients with DKC. Two had a severe form of the disorder, with additional features including growth retardation, retinopathy, ataxia, developmental delay, and cerebellar hypoplasia, consistent with a clinical diagnosis of Hoyeraal-Hreidarsson syndrome. Three patients had classic DKC, with bone marrow failure and skin and nail involvement; 2 had leukoplakia. The last 2 patients had bone marrow failure with variable features overlapping DKC, mainly nail dystrophy; 1 had intracranial calcifications. Telomere length was only available from 4 of these patients, but all showed significantly shortened telomeres. The findings indicated that TINF2 mutations can be associated with a broad spectrum of phenotypes. (less)
|
Comment:
Comment:
A Heterozygous Missense variant c.845G>A in Exon 6 of the TINF2 gene that results in the amino acid substitution p.Arg282His was identified. The observed variant has a minor allelefrequency of 0.000% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individualtools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for anindividual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. The variant has been reported to ClinVar as Pathogenic with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 5625 as of 2022-12-31). The p.R282H pathogenic mutation (also known as c.845G>A), located in coding exon 6 of the TINF2 gene, results from a G to A substitution at nucleotide position 845. The arginine at codon 282 is replaced by histidine, an amino acid with highly similar properties.This pathogenic mutation was first reported in three unrelated individuals with dyskeratosis congenita (DC) and very short telomeres (Savage, Sharon A et al., 2008; Walne, Amanda J et al., 2008; Vulliamy, T et al., 2012). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.
Comment:
PS3, PS4_moderate, PM1, PM2_supporting, PP3
Comment:
The p.R282H pathogenic mutation (also known as c.845G>A), located in coding exon 6 of the TINF2 gene, results from a G to A substitution at nucleotide position 845. The arginine at codon 282 is replaced by histidine, an amino acid with highly similar properties.This pathogenic mutation was first reported in three unrelated individuals with dyskeratosis congenita (DC) and very short telomeres (Savage SA et al. Am. J. Hum. Genet., 2008 Feb;82:501-9). Another study identified this mutation in an additional 14 individuals with DC and short telomeres; parental testing determined the majority of the identified mutations were de novo occurrences. In this cohort, individuals with this pathogenic mutation had clinically severe presentations, including individuals with Revesz syndrome and Hoyeraal-Hreidarsson syndrome (Walne AJ et al. Blood, 2008 Nov;112:3594-600). An in vitro functional study found this pathogenic mutation lead to telomere shortening, but did not affect telomerase activity, total levels of TERC, ,or cell proliferation; the authors propose telomere shortening may occur due to a defect in telomerase trafficking (Yang D et al. J. Biol. Chem., 2011 Jul;286:23022-30). Based on the supporting evidence, p.R282H is interpreted as a disease-causing mutation.
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:
This missense change has been observed in individuals with dyskeratosis congenita (PMID: 18252230, 18669893). Experimental studies have shown that this missense change affects TINF2 function (PMID: 21477109, 21536674, 29581185). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 5625). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 282 of the TINF2 protein (p.Arg282His). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg282 amino acid residue in TINF2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18669893, 19090550, 21199492, 23094712, 26859482, 29742735). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing.
Comment:
A Heterozygous Missense variant c.845G>A in Exon 6 of the TINF2 gene that results in the amino acid substitution p.Arg282His was identified. The observed variant has a minor allelefrequency of 0.000% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individualtools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for anindividual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. The variant has been reported to ClinVar as Pathogenic with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 5625 as of 2022-12-31). The p.R282H pathogenic mutation (also known as c.845G>A), located in coding exon 6 of the TINF2 gene, results from a G to A substitution at nucleotide position 845. The arginine at codon 282 is replaced by histidine, an amino acid with highly similar properties.This pathogenic mutation was first reported in three unrelated individuals with dyskeratosis congenita (DC) and very short telomeres (Savage, Sharon A et al., 2008; Walne, Amanda J et al., 2008; Vulliamy, T et al., 2012). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.
Comment:
PS3, PS4_moderate, PM1, PM2_supporting, PP3
Comment:
The p.R282H pathogenic mutation (also known as c.845G>A), located in coding exon 6 of the TINF2 gene, results from a G to A substitution at nucleotide position 845. The arginine at codon 282 is replaced by histidine, an amino acid with highly similar properties.This pathogenic mutation was first reported in three unrelated individuals with dyskeratosis congenita (DC) and very short telomeres (Savage SA et al. Am. J. Hum. Genet., 2008 Feb;82:501-9). Another study identified this mutation in an additional 14 individuals with DC and short telomeres; parental testing determined the majority of the identified mutations were de novo occurrences. In this cohort, individuals with this pathogenic mutation had clinically severe presentations, including individuals with Revesz syndrome and Hoyeraal-Hreidarsson syndrome (Walne AJ et al. Blood, 2008 Nov;112:3594-600). An in vitro functional study found this pathogenic mutation lead to telomere shortening, but did not affect telomerase activity, total levels of TERC, ,or cell proliferation; the authors propose telomere shortening may occur due to a defect in telomerase trafficking (Yang D et al. J. Biol. Chem., 2011 Jul;286:23022-30). Based on the supporting evidence, p.R282H is interpreted as a disease-causing mutation.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Clinical features of dyskeratosis congenita in mainland China: case reports and literature review. | Li F | International journal of hematology | 2019 | PMID: 30604317 |
| A case report of heterozygous TINF2 gene mutation associated with pulmonary fibrosis in a patient with dyskeratosis congenita. | Du H | Medicine | 2018 | PMID: 29742735 |
| The C-Terminal Extension Unique to the Long Isoform of the Shelterin Component TIN2 Enhances Its Interaction with TRF2 in a Phosphorylation- and Dyskeratosis Congenita Cluster-Dependent Fashion. | Nelson ND | Molecular and cellular biology | 2018 | PMID: 29581185 |
| Novel variants in Nordic patients referred for genetic testing of telomere-related disorders. | Norberg A | European journal of human genetics : EJHG | 2018 | PMID: 29483670 |
| A landscape of germ line mutations in a cohort of inherited bone marrow failure patients. | Bluteau O | Blood | 2018 | PMID: 29146883 |
| Revesz syndrome masquerading as traumatic retinal detachment. | Moussa K | Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus | 2017 | PMID: 28866069 |
| Clinical utility of gene panel-based testing for hereditary myelodysplastic syndrome/acute leukemia predisposition syndromes. | Guidugli L | Leukemia | 2017 | PMID: 28104920 |
| Clinical utility of next-generation sequencing for inherited bone marrow failure syndromes. | Muramatsu H | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 28102861 |
| Pulmonary arteriovenous malformations: an uncharacterised phenotype of dyskeratosis congenita and related telomere biology disorders. | Khincha PP | The European respiratory journal | 2017 | PMID: 27824607 |
| Robust DNA Damage Response and Elevated Reactive Oxygen Species in TINF2-Mutated Dyskeratosis Congenita Cells. | Pereboeva L | PloS one | 2016 | PMID: 26859482 |
| Reduced intensity conditioning regimen with fludarabine, cyclophosphamide, low dose TBI and alemtuzumab leading to successful unrelated umbilical cord stem cell engraftment and survival in two children with dyskeratosis congenita. | Brown M | Bone marrow transplantation | 2016 | PMID: 26808569 |
| Retinal vasculopathy in autosomal dominant dyskeratosis congenita due to TINF2 mutation. | Gleeson M | British journal of haematology | 2012 | PMID: 23094712 |
| Revertant somatic mosaicism by mitotic recombination in dyskeratosis congenita. | Jongmans MC | American journal of human genetics | 2012 | PMID: 22341970 |
| Allo-SCT in a patient with CRMCC with aplastic anemia using a reduced intensity conditioning regimen. | Asai D | Bone marrow transplantation | 2012 | PMID: 22080964 |
| Three novel truncating TINF2 mutations causing severe dyskeratosis congenita in early childhood. | Sasa GS | Clinical genetics | 2012 | PMID: 21477109 |
| Telomere length measurement can distinguish pathogenic from non-pathogenic variants in the shelterin component, TIN2. | Vulliamy T | Clinical genetics | 2012 | PMID: 21199492 |
| [Dyskeratosis congenital: clinical features and genotype analysis in two Chinese patients]. | Liu R | Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi | 2011 | PMID: 22339828 |
| TIN2 protein dyskeratosis congenita missense mutants are defective in association with telomerase. | Yang D | The Journal of biological chemistry | 2011 | PMID: 21536674 |
| A child with severe form of dyskeratosis congenita and TINF2 mutation of shelterin complex. | Sarper N | Pediatric blood & cancer | 2010 | PMID: 20979174 |
| Dyskeratosis congenita. | Savage SA | Hematology/oncology clinics of North America | 2009 | PMID: 19327580 |
| TINF2 mutations in children with severe aplastic anemia. | Du HY | Pediatric blood & cancer | 2009 | PMID: 19090550 |
| Ataxia and pancytopenia caused by a mutation in TINF2. | Tsangaris E | Human genetics | 2008 | PMID: 18979121 |
| 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 |
| TINF2, a component of the shelterin telomere protection complex, is mutated in dyskeratosis congenita. | Savage SA | American journal of human genetics | 2008 | PMID: 18252230 |
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Text-mined citations for rs121918544 ...
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Record last updated Sep 29, 2024
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