ClinVar Genomic variation as it relates to human health

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 399 of the CFTR protein (p.Ala399Val). This variant is present in population databases (rs146463120, gnomAD 0.06%). This missense change has been observed in individual(s) with idiopathic pancreatitis (PMID: 20460946). ClinVar contains an entry for this variant (Variation ID: 495889). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Variant summary: CFTR c.1196C>T (p.Ala399Val) results in a non-conservative amino acid change located in the ATP-binding cassette domain 1 (IPR047082) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 250798 control chromosomes, predominantly at a frequency of 0.00082 within the East Asian subpopulation in the gnomAD database. This frequency is not higher than the estimated maximum expected for a pathogenic variant in CFTR causing CFTR-Related Diseases (0.013), allowing no conclusion about variant significance. c.1196C>T has been reported in the literature in a patient with idiopathic pancreatitis (Pelletier_2010) and was listed to be found in a cohort of newborns with positive CF screening tests (Bozdogan_2021). In addition, the variant is cited in the SickKids database in a patient with disseminated bronchiectasis with a normal sweat chloride concentration. However no second variant was specified in these cases. These reports do not provide unequivocal conclusions about association of the variant with CFTR-Related Diseases. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20460946, 33572515). Six other submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

The p.A399V variant (also known as c.1196C>T), located in coding exon 9 of the CFTR gene, results from a C to T substitution at nucleotide position 1196. The alanine at codon 399 is replaced by valine, an amino acid with similar properties. This alteration was identified in an individual diagnosed with idiopathic pancreatitis (Pelletier AL et al. Pancreatology, 2010 May;10:158-64). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.