ClinVar Miner

Submissions for variant NM_001283009.2(RTEL1):c.1482-1G>A

dbSNP: rs863225129
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
University of Washington Center for Mendelian Genomics, University of Washington RCV000201560 SCV000256238 pathogenic Interstitial lung disease 2 2015-05-19 criteria provided, single submitter research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588351 SCV000699743 likely pathogenic Dyskeratosis congenita 2016-06-16 criteria provided, single submitter clinical testing Variant summary: The RTEL1 c.1554-1G>A variant involves the alteration of a conserved intronic nucleotide located at the invariant AG acceptor splice site of intron 17. One in silico tool predicts a damaging outcome while 3/5 splice site tools predict the variant to result in the loss of the acceptor site in intron 17 and additionally, 5/5 tools predict an activation of a cryptic splice site in exon 18 by the variant. It is absent in 117242 control chromosomes and to our knowledge, it was only reported in a family with idiopathic interstitial pneumonia. The affected family members (father and a daughter) carried the variant in heterozygosity. Persons with DKC may develop IPF and it is conceivable that IPF in a young person could be the first manifestation of DKC; thus, DKC should be considered in young persons with IPF (GeneReviews). One clinical diagnostic laboratory has classified this variant as Pathogenic. Taken together, this variant is currently classified as Likely Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV003765299 SCV004571388 likely pathogenic Dyskeratosis congenita, autosomal recessive 5; Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 2023-06-14 criteria provided, single submitter clinical testing In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 217518). Disruption of this splice site has been observed in individual(s) with pulmonary fibrosis (PMID: 25607374). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 17 of the RTEL1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in RTEL1 are known to be pathogenic (PMID: 23453664, 23959892, 25607374).

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