ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.1766G>A (p.Ser589Asn) (rs397508300)

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Total submissions: 3
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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 likely pathogenic Cystic fibrosis 2020-09-10 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 589 of the CFTR protein (p.Ser589Asn). The serine residue is moderately conserved and there is a small physicochemical difference between serine and asparagine. This variant also falls at the last nucleotide of exon 13 of the CFTR coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with cystic fibrosis, both homozygous and in combination with another CFTR variant (PMID: 16379540, 28771972, Invitae). 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: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The asparagine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID:22362925). 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.

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