ClinVar Miner

Submissions for variant NM_016434.3(RTEL1):c.2920C>T (p.Arg974Ter) (rs398123017)

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Total submissions: 6
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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 RCV000201744 SCV000256243 pathogenic Idiopathic fibrosing alveolitis, chronic form 2015-05-19 criteria provided, single submitter research
Integrated Genetics/Laboratory Corporation of America RCV000589642 SCV000699750 pathogenic Dyskeratosis congenita 2016-06-16 criteria provided, single submitter clinical testing 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.
Invitae RCV000651094 SCV000772944 pathogenic Dyskeratosis congenita, autosomal recessive, 5; Pulmonary fibrosis and/or bone marrow failure, telomere-related, 3 2019-11-18 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg998*) in the RTEL1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs398123017, ExAC 0.003%). This variant has been reported as compound heterozygous with another RTEL1 variant in individuals from two families affected with dyskeratosis congenita (PMID: 23329068, 23959892). This variant has been observed in heterozygous individuals affected with idiopathic pulmonary fibrosis (PMID: 28099038) and familial interstitial pneumonia (PMID: 25607374). This variant is also known as R974X in the literature. ClinVar contains an entry for this variant (Variation ID: 42020). Loss-of-function variants in RTEL1 are known to be pathogenic (PMID: 23453664, 23959892, 25607374). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000589642 SCV001365924 pathogenic Dyskeratosis congenita 2019-03-13 criteria provided, single submitter clinical testing 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 ( 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.
OMIM RCV000034862 SCV000058466 pathogenic Dyskeratosis congenita, autosomal recessive, 5 2013-09-03 no assertion criteria provided literature only
Counsyl RCV000034862 SCV000789457 pathogenic Dyskeratosis congenita, autosomal recessive, 5 2017-02-01 no assertion criteria provided clinical testing

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