ClinVar Genomic variation as it relates to human health

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance.

This variant has been reported to affect CFTR protein function (PMID: 9305991, 23891399, 19491324). This sequence change replaces glutamic acid with lysine at codon 193 of the CFTR protein (p.Glu193Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with cystic fibrosis or congenital bilateral absence of the vas deferrens (PMID: 7544319, 7529962). ClinVar contains an entry for this variant (Variation ID: 54006). 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.

Variant summary: CFTR c.577G>A (p.Glu193Lys) is located near a canonical splice site and results in a conservative amino acid change located in the ABC transporter type 1, transmembrane domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computational 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 250106 control chromosomes (gnomAD). c.577G>A has been reported in the literature in the compound heterozygous state in individuals affected with Cystic Fibrosis, including at least one case where it was found in trans with the pathogenic variant F508del, and in at least one individual with CBAVD (e.g. Brancolini_1995, Mercier_1995, Sofia_2018). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (e.g. Seibert_1997, Van Goor_2013). The variant results in approximately 30% of normal chloride transport activity and has a significantly reduced open probability and increased closed time compared to WT CFTR. The following publications have been ascertained in the context of this evaluation (PMID: 7544319, 7529962, 9305991, 30134826, 23891399). Four submitters, including the expert panel CFTR2, have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.