Submissions for variant NM_001283009.2(RTEL1):c.3730_3731del (p.Cys1244fs)

dbSNP: rs1316931773

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001942239	SCV002232043	pathogenic	Dyskeratosis congenita, autosomal recessive 5; Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3	2024-11-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Cys1244Profs*17) in the RTEL1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 57 amino acid(s) of the RTEL1 protein. This variant is present in population databases (no rsID available, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with clinical features of RTEL1-related conditions (PMID: 28507545, 30115091). This variant is also known as c.3724_3725delTG. This variant disrupts a region of the RTEL1 protein in which other variant(s) (p.Arg1264His) have been determined to be pathogenic (PMID: 23453664, 24009516, 25047097, 25099625, 25620558, 26025130). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV002236192	SCV002507308	likely pathogenic	Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3	2022-03-07	criteria provided, single submitter	clinical testing
GeneDx	RCV003442978	SCV004170585	pathogenic	not provided	2023-11-13	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation, as the last 57 amino acids are replaced with 16 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.3724_3725delTG, p.Cys1242Cysfs18 due to use of alternate nomenclature; This variant is associated with the following publications: (PMID: 27535533, 25620558, 28507545, 30115091, 24077912, 36496180)
Fulgent Genetics, Fulgent Genetics	RCV001942239	SCV005663986	likely pathogenic	Dyskeratosis congenita, autosomal recessive 5; Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3	2024-03-30	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004734368	SCV005342609	likely pathogenic	RTEL1-related disorder	2024-03-15	no assertion criteria provided	clinical testing	The RTEL1 c.3730_3731delTG variant is predicted to result in a frameshift and premature protein termination (p.Cys1244Profs*17). This variant has been reported in one individual with dyskeratosis congenita in the compound heterozygous state along with a second variant predicted to impact splicing (Speckmann et al. 2017. PubMed ID: 28507545) and in a second individual with immunodeficiency and shortened telomeres along with a potentially causative missense variant (described as as c.3724_3725delTG, Trotta et al. 2018. PubMed ID: 30115091). This variant is reported in 0.0047% of alleles in individuals of European (Finnish) descent in gnomAD. Frameshift variants in RTEL1 are expected to be pathogenic. This variant is interpreted as likely pathogenic.