Submissions for variant NM_001283009.2(RTEL1):c.178C>T (p.Arg60Ter)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002579263	SCV003489589	pathogenic	Dyskeratosis congenita, autosomal recessive 5; Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3	2023-01-16	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant has not been reported in the literature in individuals affected with RTEL1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Arg60*) 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).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786837	SCV005400252	pathogenic	Dyskeratosis congenita, autosomal recessive 5	2023-07-16	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal dominant dyskeratosis congenita 4 and autosomal recessive dyskeratosis congenita 5 (MIM#615190), and autosomal dominant telomere-related pulmonary fibrosis and/or bone marrow failure 3 (MIM#616373). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. Monoallelic pathogenic variants have been reported in asymptomatic family members (PMIDs: 23329068, 25848748, 35199181). (I) 0115 - Variants in this gene are known to have variable expressivity (OMIM). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other premature termination variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many NMD-predicted variants in this gene have been reported as likely pathogenic/pathogenic (ClinVar). These variants have been reported as monoallelic in individuals with short telomeres and bone marrow failure, cytopenia, myeloid neoplasms, pulmonary fibrosis or Hoyeraal-Hreidarsson syndrome, and also in healthy family members (PMIDs: 29344583, 25848748, 23329068). In addition, they have been reported in autosomal recessive inheritance (PMIDs: 23329068, 23453664). (SP) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV002579263	SCV005660948	likely pathogenic	Dyskeratosis congenita, autosomal recessive 5; Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3	2024-02-25	criteria provided, single submitter	clinical testing