ClinVar Genomic variation as it relates to human health

Variant summary: CFTR c.2908G>A (p.Gly970Ser) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. This variant also falls within exonic splice region in exon 26. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes the canonical 5' splicing donor site. One predict the variant weakens the canonical 5' donor site. One predict the variant no significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251120 control chromosomes. c.2908G>A has been reported in the literature in at-least three individuals affected with Cystic Fibrosis, without detailed information for analysis (Ortiz_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 29178639). ClinVar contains an entry for this variant (Variation ID: 53589). Based on the evidence outlined above, the variant was classified as likely pathogenic.

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 970 of the CFTR protein (p.Gly970Ser). This variant also falls at the last nucleotide of exon 17, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 29178639; Invitae). ClinVar contains an entry for this variant (Variation ID: 53589). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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 is associated with altered splicing resulting in multiple RNA products (PMID: 33085659). For these reasons, this variant has been classified as Pathogenic.

The variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in affected individuals with Cystic Fibrosis (PMID: 29178639 (2017)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

Observed in individuals with cystic fibrosis in published literature, but in whom a second CFTR variant was not specified and additional clinical information was not included (PMID: 32143663, 29178639); RNA studies demonstrate a damaging effect with partial skipping of exon 17 leading to truncated isoforms (PMID: 33085659); In silico analysis supports that this missense variant has a deleterious effect on splicing; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 29178639, 32143663, 38388235, 33085659)

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.