Submissions for variant NM_001283009.2(RTEL1):c.2413+5G>A

gnomAD frequency: 0.00002  dbSNP: rs750836127

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001938570	SCV002189148	uncertain significance	Dyskeratosis congenita, autosomal recessive 5; Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3	2022-02-07	criteria provided, single submitter	clinical testing	This sequence change falls in intron 26 of the RTEL1 gene. It does not directly change the encoded amino acid sequence of the RTEL1 protein. It affects a nucleotide within the consensus splice site. 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 variant has not been reported in the literature in individuals affected with RTEL1-related conditions. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004785380	SCV005398564	uncertain significance	Dyskeratosis congenita, autosomal recessive 5	2022-09-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal dominant and recessive dyskeratosis congenita 4 and 5 (MIM#615190) and pulmonary fibrosis and/or bone marrow failure, telomere-related, 3 (MIM#616373). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0112 - The condition associated with this gene have incomplete penetrance. This has been reported for individuals with pulmonary fibrosis (PMID: 25848748, OMIM). (I) 0212 - Non-canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (6 heterozygotes, 0 homozygotes). (SP) 0311 - An alternative nucleotide change at the same canonical splice site, is present in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0506 - Abnormal splicing is not predicted and nucleotide is poorly conserved. (SB) 0710 - Another splice variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. This alternative change (c.2413+5G>C) has been reported as a VUS (ClinVar). (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported as a VUS (ClinVar, LOVD). (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