ClinVar Genomic variation as it relates to human health

The c.581G>T; p.Gly194Val variant (rs397508763) has been reported in an individual with congenital bilateral absence of vas deferens in trans with a pathogenic variant (c.2657+5G>A) (Steiner 2011) and in an individual with elevated sweat chloride level that also carried a pathogenic p.Phe508del variant (Rychkova 2017). The p.Gly194Val variant is found on a single chromosome in the Genome Aggregation Database, indicating it is not a common polymorphism. The glycine at residue 194 is moderately conserved, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by creating a novel cryptic donor splice site. Based on available information, this variant is considered to be likely pathogenic. References: Rychkova A et al. Developing gene-specific meta-predictor of variant pathogenicity. bioRxiv. 2017 Mar 10; doi: https://doi.org/10.1101/115956. Steiner B et al. Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. Hum Mutat. 2011 Aug;32(8):912-20.

CFTR variant associated with varying clinical consequence. See www.CFTR2.org for phenotype information.

This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 194 of the CFTR protein (p.Gly194Val). This variant is present in population databases (rs397508763, gnomAD no frequency). This missense change has been observed in individuals with congenital bilateral absence of the vas deferens (PMID: 21520337, 29484681). ClinVar contains an entry for this variant (Variation ID: 54016). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.581G>T (p.Gly194Val) 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 five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251416 control chromosomes. c.581G>T has been reported in the literature in individuals affected with Congenital Bilateral Absence Of The Vas Deferens/infertility and nonobstructive azoospermia (example, Goossens_2000, Steiner_2011, Akinsal_2018, Rudnik-Schoneborn_2021, Liu_2023). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect resulted in approximately 14.2% of normal chloride channel conductance relative to wild type (e.g., Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 17003641, 21520337, 10913957, 29484681, 33374015, 33085659, 34583889, 34782259, 36259570). ClinVar contains an entry for this variant (Variation ID: 54016). Based on the evidence outlined above, the variant was classified as likely pathogenic.

This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PM2_SUP, PM3, PP3

The p.G194V variant (also known as c.581G>T), located in coding exon 6 of the CFTR gene, results from a G to T substitution at nucleotide position 581. The glycine at codon 194 is replaced by valine, an amino acid with dissimilar properties. This variant was described in two individuals with congenital bilateral absence of vas deferens in conjunction with a second CFTR variant, who also had an intronic alteration in CFTR (Steiner B et al. Hum. Mutat., 2011 Aug;32:912-20; Akinsal EC et al. Andrologia, 2018 Feb;doi: 10.1111/and.12994; Rudnik-Schöneborn S et al. Hum Reprod, 2021 Feb;36:551-559). The p.G194V variant has been reported as a variant of varying clinical consequences (VVCC) (Sosnay PR et al. Pediatr. Clin. North Am., 2016 08;63:585-98; The Clinical and Functional TRanslation of CFTR (CFTR2); available at http://cftr2.org. Accessed January 15, 2020). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, the clinical significance of this alteration remains unclear.