ClinVar Miner

Submissions for variant NM_032957.4(RTEL1):c.3028C>T (rs373740199)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000336673 SCV000329508 pathogenic not provided 2016-09-26 criteria provided, single submitter clinical testing The R1010X pathogenic variant in the RTEL1 gene has been reported previously as a heterozygous variant in two siblings with a presumed dominantly inherited form of dyskeratosis congenita and Hoyeraal-Hreidarsson syndrome with thrombocytopenia, anemia, severe bone marrow failure, delays, microcephaly, and cerebellar hypoplasia (Ballew et al., 2013). This variant was also found in their mother who had shortened telomeres but was clinically unaffected. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R1010X variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry by the NHLBI Exome Sequencing Project. We interpret R1010X as a pathogenic variant.
Genetic Services Laboratory, University of Chicago RCV000502656 SCV000596853 pathogenic Dyskeratosis congenita 2016-03-22 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000502656 SCV000699751 likely pathogenic Dyskeratosis congenita 2016-06-16 criteria provided, single submitter clinical testing Variant summary: The RTEL1 c.3028C>T (p.Arg1010X) 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. A protein truncation would result in the loss of the PCNA (proliferating cell nuclear antigen) interacting protein (PIP) motif. This variant was found in 10/119716 control chromosomes at a frequency of 0.0000835, which does not exceed the estimated maximal expected allele frequency of a pathogenic RTEL1 variant (0.001118). The variant has been reported in three patients with Dyskeratosis congenital, two were siblings from a family who had this maternally transmitted variant in heterozygous state (other mutation was not identified by WES, but MLPA was not carried out) and another was compound heterozygous with p.Ile449Thr. Additionally, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as Likely Pathogenic.
Invitae RCV000703852 SCV000832776 pathogenic Dyskeratosis congenita, autosomal recessive, 5; Pulmonary fibrosis and/or bone marrow failure, telomere-related, 3 2020-10-16 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg986*) in the RTEL1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs373740199, ExAC 0.03%). This variant has been observed in individuals affected with shortened telomeres and Hoyeraal-Hreidarsson syndrome, shortened telomeres and early onset ulcerative colitis, or idiopathic pulmonary fibrosis (PMID: 23329068, 28930861, 27128385, 28099038). This variant is also known as c.3028C>T, p.Arg1010*, and R1010X in the literature. ClinVar contains an entry for this variant (Variation ID: 65417). 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.
Baylor Genetics RCV000665130 SCV001163816 pathogenic Dyskeratosis congenita, autosomal recessive, 5 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000336673 SCV001249247 pathogenic not provided 2020-01-01 criteria provided, single submitter clinical testing
OMIM RCV000055639 SCV000083862 pathogenic Dyskeratosis congenita, autosomal dominant, 4 2013-04-01 no assertion criteria provided literature only
Counsyl RCV000665130 SCV000789196 likely pathogenic Dyskeratosis congenita, autosomal recessive, 5 2017-01-25 no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000336673 SCV001952736 pathogenic not provided no assertion criteria provided clinical testing

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