Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Mendelics | RCV000757839 | SCV000886328 | pathogenic | Cystic fibrosis | 2018-11-05 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV000757839 | SCV002615486 | likely pathogenic | Cystic fibrosis | 2023-10-30 | criteria provided, single submitter | clinical testing | The c.3367+1G>A intronic variant (also known as 3499+1G>A) results from a G to A substitution one nucleotide after coding exon 20 of the CFTR gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000757839 | SCV004241049 | likely pathogenic | Cystic fibrosis | 2023-12-13 | criteria provided, single submitter | clinical testing | Variant summary: CFTR c.3367+1G>A 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. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 249524 control chromosomes. c.3367+1G>A has been reported in the literature in individuals affected with Cystic Fibrosis (Da Silva_2021, Sala_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Labcorp Genetics |
RCV000757839 | SCV004428489 | pathogenic | Cystic fibrosis | 2025-01-06 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 20 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). This variant is present in population databases (no rsID available, gnomAD 0.01%). Disruption of this splice site has been observed in individuals with cystic fibrosis (PMID: 32819855, 33495079; internal data). This variant is also known as 3499+1G>A. ClinVar contains an entry for this variant (Variation ID: 618936). 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. |