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.

the variant causes a phenotype but regarding our data, we can't formally attribute it to CF, CFTR-RD or both

The p.D110E variant (also known as c.330C>A), located in coding exon 4 of the CFTR gene, results from a C to A substitution at nucleotide position 330. The aspartic acid at codon 110 is replaced by glutamic acid, an amino acid with highly similar properties. This variant has been identified in multiple individuals, including one homozygous individual with borderline sweat chloride levels and no lung disease (Padoan R et al. Hum. Mutat., 2000 May;15:485; Padoan R et al. Acta Paediatr, 2002;91:82-7; Poulou M et al. J. Cyst. Fibros., 2012 Jul;11:344-8). Functional studies demonstrated that this variant results in reduced CFTR channel function, compared to wild-type protein (Cui G et al. J. Gen. Physiol., 2014 Aug;144:159-79; Van Goor F et al. J. Cyst. Fibros., 2014 Jan;13:29-36; Raraigh KS et al. Am. J. Hum. Genet., 2018 06;102:1062-1077). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 110 of the CFTR protein (p.Asp110Glu). This variant is present in population databases (rs397508537, gnomAD 0.003%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 10790222, 11883825). ClinVar contains an entry for this variant (Variation ID: 53714). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CFTR protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects CFTR function (PMID: 23891399, 29805046). 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. For these reasons, this variant has been classified as Pathogenic.

Variant summary: CFTR c.330C>A (p.Asp110Glu) results in a 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 damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251104 control chromosomes (gnomAD). c.330C>A has been reported in the literature in multiple individuals affected with varying phenotypes, predominantly presenting as a mild phenotype, which patients have a borderline sweat chloride level, pancreatic sufficiency, and normal lung function (Colombo_2006, Padoan_2002, Sermet-Gaudelus__2010, Tzetis_2001, Xie_2015, McCague_2019). These data indicate that the variant is very likely to be associated with disease. However, functional studies have indicated that the variant greater affects chloride transport (van Goor_2013, Raraigh_2018) and significantly longer mean burst durations (Cui_2014 and Infield_2016). Authors further go on to state "the structure of ECL1 must be tuned delicately to maintain function...none of the charge-retaining mutations identified in ECL1 are able to completely rescue the mutant channel behavior to that of WT-CFTR. This is likely the result of a requirement for very specific bond angles within a network of charged residues that control the architecture of ECL1"(Cui_2014)." Furthermore, another variant at this location D110H has been classified as "pathogenic" by LCA, along with another variant being reported D110R (Cui_2014), therefore, suggesting this location is a mutational hotspot and important for protein function. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (1x) and pathogenic (2x). Based on the evidence outlined above, the variant was classified as pathogenic.

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

The c.330C>A variant in CFTR is a missense variant predicted to cause substitution of aspartic acid to glutamic acid at amino acid 110. This variant is rare in the general population with a frequency below the threshold expected for the associated phenotype(s). This variant has been observed in one or more individuals affected with the associated recessive disease, as either homozygous or compound heterozygous with a second variant (PMID: 10790222). Functional studies show that this variant may disrupt protein function (PMID: 29805046). Another variant at this same site results in an alteration predicted to cause a similar molecular effect has been observed in individual(s) with the associated phenotype. A different variant at the same position has been determined to be Pathogenic or Likely Pathogenic. Computational prediction algorithms indicate this variant is likely to affect gene or protein function. Given the available evidence, this variant is classified as Pathogenic.

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.