Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000507002 | SCV000601061 | uncertain significance | not specified | 2017-04-21 | criteria provided, single submitter | clinical testing | |
| Mendelics | RCV000757803 | SCV000886274 | pathogenic | Cystic fibrosis | 2018-11-05 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000757803 | SCV001574749 | pathogenic | Cystic fibrosis | 2023-10-03 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 589 of the CFTR protein (p.Ser589Asn). RNA analysis indicates that this missense change induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with cystic fibrosis (PMID: 16379540, 30711384; Invitae). This variant is also known as G1898A. ClinVar contains an entry for this variant (Variation ID: 53382). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exon 12, but is expected to preserve the integrity of the reading-frame (PMID: 22362925). For these reasons, this variant has been classified as Pathogenic. |
| Genome- |
RCV000757803 | SCV001822084 | likely pathogenic | Cystic fibrosis | 2021-07-22 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000757803 | SCV003929009 | pathogenic | Cystic fibrosis | 2023-04-20 | criteria provided, single submitter | clinical testing | Variant summary: CFTR c.1766G>A (p.Ser589Asn) results in a conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. As the variant alters the last conserved nucleotide of exon 13 adjacent to the canonical splice donor site, several computational tools predict a significant impact on normal splicing: Three predict the variant weakens the canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing by severely reducing exon inclusion (FernandezAlanis_2012). The variant was absent in 249234 control chromosomes. c.1766G>A has been reported in the literature as a homozygous or compound heterozygous genotype in multiple individuals affected with Cystic Fibrosis (example, Stanziale_2005, Merelle_2006, Nunes_2017, Miller_2019). These data indicate that the variant is very likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (P/LP, n=4; VUS, n=1). Based on the evidence outlined above, the variant was classified as pathogenic. |
| Baylor Genetics | RCV003473467 | SCV004213568 | likely pathogenic | Bronchiectasis with or without elevated sweat chloride 1 | 2023-02-11 | criteria provided, single submitter | clinical testing | |
| Natera, |
RCV001826626 | SCV002080672 | likely pathogenic | CFTR-related disorders | 2019-06-21 | no assertion criteria provided | clinical testing |