Submissions for variant NM_001283009.2(RTEL1):c.2851+1G>A

dbSNP: rs1421904176

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002238667	SCV002511905	likely pathogenic	Dyskeratosis congenita	2022-04-17	criteria provided, single submitter	clinical testing	Variant summary: RTEL1 c.2923+1G>A (NM_001283009.2(RTEL1):c.2851+1G>A) alters a conserved nucleotide located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 249044 control chromosomes. To our knowledge, no occurrence of c.2923+1G>A in individuals affected with Dyskeratosis Congenita (Hoyeraal Hreidarsson Syndrome) and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003774689	SCV004589383	likely pathogenic	Dyskeratosis congenita, autosomal recessive 5; Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3	2023-02-26	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1683384). This variant has not been reported in the literature in individuals affected with RTEL1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 29 of the RTEL1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in RTEL1 are known to be pathogenic (PMID: 23453664, 23959892, 25607374).