Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc).;For recessive disorders, detected in trans with a pathogenic variant.;Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.;Patient's phenotype or family history is highly specific for a disease with a single genetic etiology.

Variant summary: CFTR c.592G>C (p.Ala198Pro) results in a non-conservative amino acid change in 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 4e-06 in 251444 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.592G>C has been reported in the literature in individuals affected with Congenital Absence Of The Vas Deferens without strong evidence of causality (e.g. Ooi_2014, Yang_2015, Fang_2022, Wilschanski_2006, Luo_2021, Yang_2018). These reports do not provide unequivocal conclusions about association of the variant with Congenital Bilateral Absence Of The Vas Deferens. 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: 22504961, 26277102, 36437957, 16840743, 32777524, 30450785). Four 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.

ClinVar contains an entry for this variant (Variation ID: 54017). 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 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. This missense change has been observed in individual(s) with congenital bilateral absence of the vas deferens (PMID: 16840743, 25898554, 30450785). This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 198 of the CFTR protein (p.Ala198Pro). This variant is present in population databases (rs193922529, gnomAD 0.01%).