ClinVar Genomic variation as it relates to human health

The CFTR c.328G>T variant is predicted to result in the amino acid substitution p.Asp110Tyr. In the literature this variant is also reported as c.460G>T and D110Y. This variant has been reported along with the CFTR ∆F508 variant in an individual with congenital absence of the vas deferens (CAVD) (Casals et al. 2000. PubMed ID: 10875853). However, in a large study of individuals with infertility, this variant was reported in the control population (Morea et al. 2005. PubMed ID: 16126774). Functional studies have shown the p.Asp110Tyr variant leads to CFTR channel instability (Cui et al. 2014. PubMed ID: 25024266). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-117171007-G-T) and is reported with conflicting interpretations regarding its pathogenicity in ClinVar, ranging from uncertain to likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/53705/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

PP3, PM2, PM3_supporting, PM5

Variant summary: CFTR c.328G>T (p.Asp110Tyr) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) 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 4e-06 in 251100 control chromosomes. c.328G>T has been reported in the literature in compound heterozygous individuals affected with CAVD and CF, several of whom carrry F508Del as second allele (Casals_2000, Qu_2023, Bauer_2021, Raraigh_2022). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two variants at same codon have been classified as pathogenic by our lab: (p.Asp110His, p.Asp110Glu). The following publications have been ascertained in the context of this evaluation (PMID: 33512069, 10875853, 25024266, 22483971, 27157324, 16126774, 36604502, 25735457, 34782259). ClinVar contains an entry for this variant (Variation ID: 53705). Based on the evidence outlined above, the variant was classified as pathogenic.

The p.D110Y variant (also known as c.328G>T), located in coding exon 4 of the CFTR gene, results from a G to T substitution at nucleotide position 328. The aspartic acid at codon 110 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration in men with congenital absence of the vas deferens (CAVD) (Casals T et al. Hum Reprod. 2000;15(7):1476-83; Feng J et al. Reproduction, 2022 Sep;164:R47-R56). 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.

This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 110 of the CFTR protein (p.Asp110Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with congenital bilateral absence of the vas deferens (CBAVD) and/or cystic fibrosis (PMID: 10875853, 34782259). ClinVar contains an entry for this variant (Variation ID: 53705). 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 with a positive predictive value of 80%. This variant disrupts the p.Asp110 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9272157, 18373402, 19897426, 22724884). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.