ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.2490+1G>T

dbSNP: rs141158996
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Johns Hopkins Genomics, Johns Hopkins University RCV001250517 SCV001425311 pathogenic Cystic fibrosis 2020-03-09 criteria provided, single submitter clinical testing CFTR c.2490+1G>T has been previously identified in a patient with cystic fibrosis. This CFTR variant (rs141158996) is rare (<0.1%) in a large population dataset (gnomAD: 1/190386 total alleles; 0.0005%; no homozygotes). This variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing. We consider this variant to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV001250517 SCV003480730 pathogenic Cystic fibrosis 2022-06-10 criteria provided, single submitter clinical testing 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. ClinVar contains an entry for this variant (Variation ID: 973859). This variant is also known as c.2622+1G>T. Disruption of this splice site has been observed in individuals with cystic fibrosis (PMID: 7683952, 9239681, 12815607, 20059485, 23974870). 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 affects a donor splice site in intron 14 of the CFTR 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 CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922).
Baylor Genetics RCV004570640 SCV005057413 pathogenic Bronchiectasis with or without elevated sweat chloride 1 2024-03-20 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001250517 SCV005883994 pathogenic Cystic fibrosis 2024-12-31 criteria provided, single submitter clinical testing Variant summary: CFTR c.2490+1G>T is 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of CFTR function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 5.3e-06 in 190386 control chromosomes. c.2490+1G>T also known as c.2622+1G>T has been reported in the literature in individuals affected with Cystic Fibrosis (examples: Scotet_2003, Soultan_2008, Raraigh_2021). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 12815607, 34782259, 19014821). ClinVar contains an entry for this variant (Variation ID: 973859). Based on the evidence outlined above, the variant was classified as pathogenic.
PreventionGenetics, part of Exact Sciences RCV004538530 SCV004712081 pathogenic CFTR-related disorder 2023-12-21 no assertion criteria provided clinical testing The CFTR c.2490+1G>T variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in individuals undergoing genetic testing for cystic fibrosis (referred to as c.2622+1G>T in Scotet et al. 2003. PubMed ID: 12815607; Table S4, Raraigh et al. 2021. PubMed ID: 34782259). This variant is reported in 0.0011% of alleles in individuals of European (non-Finnish) descent in gnomAD and is interpreted as pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/973859/). Variants that disrupt the consensus splice donor site in CFTR are expected to be pathogenic. This variant is interpreted as pathogenic.

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