Submissions for variant NM_001283009.2(RTEL1):c.2956C>T (p.Arg986Ter)

gnomAD frequency: 0.00009  dbSNP: rs373740199

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000336673	SCV000329508	pathogenic	not provided	2023-12-29	criteria provided, single submitter	clinical testing	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; Also known as R986X; This variant is associated with the following publications: (PMID: 25607374, 27128385, 29146883, 28099038, 25940403, 25244922, 29344583, 28495916, 28930861, 30523160, 28104920, 31785789, 23329068)
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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000703852	SCV000832776	pathogenic	Dyskeratosis congenita, autosomal recessive 5; Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3	2024-11-05	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. Loss-of-function variants in RTEL1 are known to be pathogenic (PMID: 23453664, 23959892, 25607374). This variant is present in population databases (rs373740199, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with shortened telomeres and Hoyeraal-Hreidarsson syndrome, shortened telomeres and early onset ulcerative colitis, or idiopathic pulmonary fibrosis (PMID: 23329068, 27128385, 28099038, 28930861). This variant is also known as c.3028C>T, p.Arg1010*, and R1010X. ClinVar contains an entry for this variant (Variation ID: 65417). 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.
Baylor Genetics	RCV000665130	SCV001163816	pathogenic	Dyskeratosis congenita, autosomal recessive 5	2024-03-25	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000336673	SCV001249247	pathogenic	not provided	2024-01-01	criteria provided, single submitter	clinical testing	RTEL1: PVS1, PS4:Moderate
Revvity Omics, Revvity	RCV000336673	SCV002019909	pathogenic	not provided	2023-06-23	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000703852	SCV002810432	pathogenic	Dyskeratosis congenita, autosomal recessive 5; Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3	2022-05-04	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000336673	SCV004227689	pathogenic	not provided	2024-07-03	criteria provided, single submitter	clinical testing	PP1, PS4, PVS1
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000336673	SCV004242574	pathogenic	not provided	2025-03-04	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000665130	SCV005398091	pathogenic	Dyskeratosis congenita, autosomal recessive 5	2020-05-21	criteria provided, single submitter	clinical testing	A heterozygous nonsense variant was identified, NM_016434.3(RTEL1):c.2956C>T in exon 30 of 35 of the RTEL1 gene. This nonsense variant is predicted to create a change of an arginine to a stop at amino acid position 986 of the protein; NP_057518.1(RTEL1):p.(Arg986*), resulting in the loss of normal protein function through nonsense-mediated decay (NMD). The variant is present in the gnomAD population database at a global population frequency of 0.008% (22 heterozygotes; 0 homozygotes) with a European (Finnish) sub-population frequency of 0.03%. The variant has been previously reported in patients with RTEL1-related disorders, and has been shown to have incomplete penetrance and variable expressivity (ClinVar, Ballew, B. et al. (2013), Moriya, K. et al. (2016), Cardoso, S. et al. (2017), Petrovski, S. et al. (2017), Petersen, B. et al. (2017), Marsh, J. et al. (2018)). In addition, studies have shown that individuals with this variant have shortened telomeres (Ballew, B. et al. (2013), Cardoso, S. et al. (2017)). Other variants predicted to cause NMD have also been reported as pathogenic (ClinVar). Based on information available at the time of curation, this variant has been classified as PATHOGENIC.
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
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000336673	SCV001952736	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000336673	SCV001965627	pathogenic	not provided		no assertion criteria provided	clinical testing
Garcia Pulmonary Genetics Research Laboratory, Columbia University Irving Medical Center	RCV002509196	SCV002547362	pathogenic	Pulmonary fibrosis	2022-06-09	no assertion criteria provided	research	Leukocyte telomere length (by qPCR) less than 10th percentile age-adjusted
PreventionGenetics, part of Exact Sciences	RCV004537250	SCV004115336	pathogenic	RTEL1-related disorder	2024-02-23	no assertion criteria provided	clinical testing	The RTEL1 c.3028C>T variant is predicted to result in premature protein termination (p.Arg1010*). In the literature, this variant is also reported as p.986*, using a different transcript (NM_001283009.1). This variant has been reported in two siblings with dyskeratosis congenita and Hoyeraal-Hreidarsson syndrome and was also reported in their unaffected mother (Ballew et al. 2013. PubMed ID: 23329068). This variant has also been reported in a family with interstitial lung disease, bone marrow failure, and ulcerative colitis (Borie et al. 2019. PubMed ID: 30523160; Marsh et al. 2018. PubMed ID: 29344583; Petersen et al. 2017. PubMed ID: 28930861). In one report, patients with the c.3028C>T variant also had shorted telomere lengths consistent with disease (Marsh et al. 2018. PubMed ID: 29344583). This variant is reported in 0.032% of alleles in individuals of European (Finnish) descent in gnomAD and is interpreted as pathogenic/likely pathogenic by multiple laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/65417/). Nonsense variants in RTEL1 are expected to be pathogenic. This variant is interpreted as pathogenic.