ClinVar Genomic variation as it relates to human health

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 287 of the CFTR protein (p.Asn287Lys). This variant is present in population databases (rs112162204, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with CFTR-related conditions. ClinVar contains an entry for this variant (Variation ID: 54071). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CFTR protein function. 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.

The frequency of this variant in the general population, 0.0017 (33/19904 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with cystic fibrosis (CF) (PMID: 26708955 (2016)), congenital bilateral absence of the vas deferens (CBAVD) (PMID: 15905293 (2005) 32777524, (2021)), enteric fever (PMID: 20233062 (2010)), and intrahepatic cholestasis (PMID: 31450232 (2020)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.

Variant summary: CFTR c.861C>G (p.Asn287Lys) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 248836 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Chronic Pancreatitis Risk (0.00011 vs 0.0063), allowing no conclusion about variant significance. c.861C>G has been reported in the literature in individuals affected with CBAVD, cystic fibrosis, enteric fever and intrahepatic cholestasis (e.g. Wu_2005, van de Vosse_2010, Schrijver_2016, Wang_2020, Luo_2021). These reports do not provide unequivocal conclusions about association of the variant with disease. 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: 32777524, 26708955, 31450232, 15905293, 20233062). ClinVar contains an entry for this variant (Variation ID: 54071). Based on the evidence outlined above, the variant was classified as uncertain significance.

The p.N287K variant (also known as c.861C>G), located in coding exon 7 of the CFTR gene, results from a C to G substitution at nucleotide position 861. The asparagine at codon 287 is replaced by lysine, an amino acid with similar properties. This variant was identified in a Taiwanese man with congenital bilateral absence of the vas deferens; a second CFTR alteration was not detected (Wu CC et al. Hum. Reprod., 2005 Sep;20:2470-5). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

CFTR c.861C>G has been identified as a single heterozygous variant in multiple individuals with congenital bilateral absence of the vas deferens and has been reported in ClinVar (Variation ID: 54071). This variant (rs112162204) has been identified in a large population dataset and the minor allele frequency is neither low enough to consider the variant rare (<0.1%) nor high enough to consider it a population polymorphism (>1%) within the East Asian subpopulation (gnomAD: 33/19904 alleles; 0.1658%, no homozygotes). Three bioinformatic tools queried predict that this substitution would be tolerated, while the asparagine residue at this position is evolutionarily conserved across many of the species assessed. We consider the clinical significance of CFTR c.861C>G to be uncertain at this time.

In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with congenital bilateral absence of the vas deferens (CBAVD) without a second CFTR variant identified and in patients with CAVD, cystic fibrosis, or intrahepatic cholestasis with no information provided on whether other CFTR variants were also identified (Wu et al., 2005; Schrijver et al., 2016; Wang et al., 2020; Luo et al., 2021); This variant is associated with the following publications: (PMID: 35913788, 15905293, 32777524, 26708955, 26471113, 29216686, 20233062, 35313924, 31450232)