ClinVar Genomic variation as it relates to human health
NM_001283009.2(RTEL1):c.2920C>T (p.Arg974Ter)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001283009.2(RTEL1):c.2920C>T (p.Arg974Ter)
Variation ID: 42020 Accession: VCV000042020.51
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 20q13.33 20: 63693211 (GRCh38) [ NCBI UCSC ] 20: 62324564 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Nov 9, 2015 May 12, 2024 Mar 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001283009.2:c.2920C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001269938.1:p.Arg974Ter nonsense NM_001283010.1:c.2251C>T NP_001269939.1:p.Arg751Ter nonsense NM_016434.4:c.2920C>T NP_057518.1:p.Arg974Ter nonsense NM_032957.5:c.2992C>T NP_116575.3:p.Arg998Ter nonsense NR_037882.1:n.3747C>T non-coding transcript variant NC_000020.11:g.63693211C>T NC_000020.10:g.62324564C>T NG_033901.1:g.40402C>T NG_046961.1:g.1561C>T LRG_1149:g.40402C>T LRG_1149t1:c.2992C>T LRG_1149p1:p.Arg998Ter LRG_1149t2:c.2920C>T LRG_1149p2:p.Arg974Ter LRG_1149t3:c.2920C>T LRG_1149p3:p.Arg974Ter - Protein change
- R998*, R974*, R751*
- Other names
- p.Arg974*
- Canonical SPDI
- NC_000020.11:63693210:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00009
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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. |
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RTEL1 | - | - |
GRCh38 GRCh37 |
13 | 3290 | |
RTEL1-TNFRSF6B | - | - | - | GRCh38 | - | 3596 |
Conditions - Germline
Condition
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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. |
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Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Oct 9, 2023 | RCV000034862.13 | |
Pathogenic (1) |
criteria provided, single submitter
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May 19, 2015 | RCV000201744.2 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Mar 13, 2019 | RCV000589642.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 22, 2024 | RCV000651094.9 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Mar 1, 2024 | RCV001558635.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 9, 2022 | RCV002509182.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 29, 2023 | RCV003492338.1 |
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. |
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Pathogenic
(May 19, 2015)
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criteria provided, single submitter
Method: research
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Interstitial lung disease 2
Affected status: yes
Allele origin:
inherited
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University of Washington Center for Mendelian Genomics, University of Washington
Accession: SCV000256243.1
First in ClinVar: Nov 09, 2015 Last updated: Nov 09, 2015 |
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Pathogenic
(Mar 13, 2019)
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criteria provided, single submitter
Method: clinical testing
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Dyskeratosis congenita
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV001365924.1
First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020 |
Comment:
The p.Arg998X variant in RTEL1 has been reported in the compound heterozygous state in 3 individuals with dyskeratosis congenita or Hoyeraal-Hreidarsson syndrome (Walne 2013, Ballew … (more)
The p.Arg998X variant in RTEL1 has been reported in the compound heterozygous state in 3 individuals with dyskeratosis congenita or Hoyeraal-Hreidarsson syndrome (Walne 2013, Ballew 2013, Deng 2013) and segregated disease in 5 affected relatives from 2 families (Walne 2013, Deng 2013). It was also identified in the heterozygous state in 3 individuals with pulmonary fibrosis (Petrovski 2017). In vitro functional studies provide evidence that the p.Arg998X variant impacts protein function (Deng 2013). This variant has also been identified in 6/125600 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org)and reported in ClinVar (Variation ID #42020). This nonsense variant leads to a premature termination codon at position 998 which is predicted to lead to a truncated or absent protein. Loss of function of the RTEL1 gene is an established disease mechanism in autosomal recessive dyskeratosis congenita. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive dyskeratosis congenita. ACMG/AMP Criteria applied: PVS1, PM2, PM3_Strong, PS3_Supporting, PP1_Strong. (less)
Number of individuals with the variant: 2
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Pathogenic
(Jan 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Dyskeratosis congenita, autosomal recessive 5
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002059023.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000042020, PMID:23453664). Stop-gained (nonsense): … (more)
The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000042020, PMID:23453664). Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000032, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Abnormal pulmonary interstitial morphology (present) , Cirrhosis of liver (present) , Pancytopenia (present)
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Pathogenic
(Oct 09, 2023)
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criteria provided, single submitter
Method: clinical testing
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Dyskeratosis congenita, autosomal recessive 5
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004209337.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Mar 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004810804.2
First in ClinVar: Apr 15, 2024 Last updated: May 12, 2024 |
Comment:
RTEL1: PVS1, PM2, PS4:Moderate, PS3:Supporting
Number of individuals with the variant: 1
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Pathogenic
(Jun 16, 2016)
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criteria provided, single submitter
Method: clinical testing
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Dyskeratosis congenita
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000699750.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The RTEL1 c.2992C>T (p.Arg998X) variant results in a premature termination codon, predicted to cause a truncated or absent RTEL1 protein due to nonsense … (more)
Variant summary: The RTEL1 c.2992C>T (p.Arg998X) variant results in a premature termination codon, predicted to cause a truncated or absent RTEL1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The functional study showed that R974X transcript was degraded by nonsense-mediated decay (Deng_2013), and cells with variant showed significantly shortening telomeres (Deng_2013, Walne_2013) compare to WT. One in silico tool predicts a damaging outcome for this variant. This variant was found in 2/119914 control chromosomes at a frequency of 0.0000167, which does not exceed the estimated maximal expected allele frequency of a pathogenic RTEL1 variant (0.001118). This variant has been reported in multiple affected individuals with HHS and the variant was shown to co-segregate with disease in at least two families. In addition, one clinical diagnostic laboratory classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
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Pathogenic
(Jun 09, 2022)
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criteria provided, single submitter
Method: research
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Pulmonary fibrosis
Affected status: yes
Allele origin:
germline
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Garcia Pulmonary Genetics Research Laboratory, Columbia University Irving Medical Center
Accession: SCV002547359.1
First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023 |
Comment:
Pathogenic criteria: null variant (PVS1) with functional study supportive of damaging effect (PS3): leukocyte telomere length (by qPCR) less than 10th percentile age-adjusted
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Pathogenic
(Feb 02, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001780628.4
First in ClinVar: Aug 14, 2021 Last updated: Nov 25, 2023 |
Comment:
Published functional studies demonstrate a damaging effect on telomere function, structure, and length (PMID: 23959892); Nonsense variant predicted to result in protein truncation or nonsense … (more)
Published functional studies demonstrate a damaging effect on telomere function, structure, and length (PMID: 23959892); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 23453664, 23329068, 30995915, 25607374, 23959892, 29344583, 33718801, 36090019, 28099038, 25047097) (less)
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Pathogenic
(Nov 29, 2023)
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criteria provided, single submitter
Method: clinical testing
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Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3
Affected status: unknown
Allele origin:
germline
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Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV004239045.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
Comment:
This RTEL1 variant has been reported in the literature in individuals with autosomal dominant as well as recessive RTEL1-related disorders. It (rs398123017) has been reported … (more)
This RTEL1 variant has been reported in the literature in individuals with autosomal dominant as well as recessive RTEL1-related disorders. It (rs398123017) has been reported in ClinVar (Variation ID 42020), and is rare (<0.1%) in a large population dataset (gnomAD v4.0.0: 92/1611994 total alleles; 0.006%; no homozygotes). This nonsense variant results in a premature stop codon in exon 30 of 35, likely leading to nonsense-mediated decay and lack of protein production, which is supported by a functional study. We consider c.2920C>T in RTEL1 to be pathogenic. (less)
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Pathogenic
(Jan 22, 2024)
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criteria provided, single submitter
Method: clinical testing
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Dyskeratosis congenita, autosomal recessive 5
Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000772944.8
First in ClinVar: May 28, 2018 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg974*) in the RTEL1 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg974*) in the RTEL1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RTEL1 are known to be pathogenic (PMID: 23453664, 23959892, 25607374). This variant is present in population databases (rs398123017, gnomAD 0.005%). This premature translational stop signal has been observed in individuals with dyskeratosis congenita, familial interstitial pneumonia, and/or idiopathic pulmonary fibrosis (PMID: 23329068, 23959892, 25607374, 28099038). It has also been observed to segregate with disease in related individuals. This variant is also known as R974X. ClinVar contains an entry for this variant (Variation ID: 42020). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Sep 03, 2013)
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no assertion criteria provided
Method: literature only
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DYSKERATOSIS CONGENITA, AUTOSOMAL RECESSIVE 5
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000058466.6
First in ClinVar: May 03, 2013 Last updated: Oct 07, 2016 |
Comment on evidence:
For discussion of the arg998-to-ter (R998X) mutation in the RTEL1 gene that was found in compound heterozygous state in patients with autosomal recessive dyskeratosis congenita-5 … (more)
For discussion of the arg998-to-ter (R998X) mutation in the RTEL1 gene that was found in compound heterozygous state in patients with autosomal recessive dyskeratosis congenita-5 (DKCB5; 615190) by Walne et al. (2013) and Ballew et al. (2013), see 608833.0003 and 608833.0011, respectively. This mutation was also found in compound heterozygous state by Deng et al. (2013) and referred to as ARG974TER; see 608833.0003. (less)
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Pathogenic
(Feb 01, 2017)
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no assertion criteria provided
Method: clinical testing
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Dyskeratosis congenita, autosomal recessive 5
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000789457.2
First in ClinVar: Oct 07, 2016 Last updated: Oct 07, 2016 |
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Dyskeratosis congenita
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001456918.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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
HelpTitle | Author | Journal | Year | Link |
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Lung transplant recipients with telomere-mediated pulmonary fibrosis have increased risk for hematologic complications. | Hannan SJ | American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons | 2023 | PMID: 37392813 |
Dyskeratosis congenita with heterozygous RTEL1 mutations presenting with fibrotic hypersensitivity pneumonitis. | Han J | Respiratory medicine case reports | 2023 | PMID: 36655009 |
Heterozygous RTEL1 variants in bone marrow failure and myeloid neoplasms. | Marsh JCW | Blood advances | 2018 | PMID: 29344583 |
An Exome Sequencing Study to Assess the Role of Rare Genetic Variation in Pulmonary Fibrosis. | Petrovski S | American journal of respiratory and critical care medicine | 2017 | PMID: 28099038 |
Rare variants in RTEL1 are associated with familial interstitial pneumonia. | Cogan JD | American journal of respiratory and critical care medicine | 2015 | PMID: 25607374 |
Carrier screening of RTEL1 mutations in the Ashkenazi Jewish population. | Fedick AM | Clinical genetics | 2015 | PMID: 25047097 |
Inherited mutations in the helicase RTEL1 cause telomere dysfunction and Hoyeraal-Hreidarsson syndrome. | Deng Z | Proceedings of the National Academy of Sciences of the United States of America | 2013 | PMID: 23959892 |
Constitutional mutations in RTEL1 cause severe dyskeratosis congenita. | Walne AJ | American journal of human genetics | 2013 | PMID: 23453664 |
Germline mutations of regulator of telomere elongation helicase 1, RTEL1, in Dyskeratosis congenita. | Ballew BJ | Human genetics | 2013 | PMID: 23329068 |
Text-mined citations for rs398123017 ...
HelpRecord last updated May 12, 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.