ClinVar Genomic variation as it relates to human health

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 479 of the CFTR protein (p.Glu479Asp). This variant is present in population databases (rs754152822, gnomAD 0.04%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 30763667). ClinVar contains an entry for this variant (Variation ID: 439478). 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 not 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.

In silico analysis supports that this missense variant does not alter protein structure/function; Observed in the heterozygous state in a patient with suspected cystic fibrosis and with a pathogenic CFTR variant (phase unknown) in an asymptomatic individual (Schwartz 2009, Ruiz-Cabezas 2019); This variant is associated with the following publications: (PMID: 27535533, 19324992, 30763667)

Variant summary: CFTR c.1437G>C (p.Glu479Asp) results in a conservative amino acid change located in the ABC transporter-like, ATP-binding domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251304 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (5.6e-05 vs 0.013), allowing no conclusion about variant significance. c.1437G>C has been reported in the literature in an asymptomatic individual without any clinical symptoms of CF, undergoing carrier screening, initially identified on basis of a false positive homozygosity for p.Phe508del allele and subsequently found to harbor one copy of this variant with p.Phe508del (Schwartz_2009). It has also been reported as a non-informative genotype (second allele/zygosity not specified) in the Ecuadorian Cystic Fibrosis Foundation cohort (Ruiz-Cabezas_2019). These reports do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. 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: 30763667, 19324992). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

The p.E479D variant (also known as c.1437G>C), located in coding exon 11 of the CFTR gene, results from a G to C substitution at nucleotide position 1437. The glutamic acid at codon 479 is replaced by aspartic acid, an amino acid with highly similar properties. This variant was detected in an individual without clinical symptoms of cystic fibrosis in conjunction with the p.F508del mutation; however, the phase of the alterations was not provided (Schwartz KM et al. J Mol Diagn, 2009 May;11:211-5). This variant was also detected in the heterozygous state in an individual with cystic fibrosis (Ruiz-Cabezas JC et al. Gene, 2019 May;696:28-32). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

The CFTR c.1437G>C variant is predicted to result in the amino acid substitution p.Glu479Asp. This variant has been reported in individuals with Cystic fibrosis (Schwartz et al. 2009. PubMed ID: 19324992; Ruiz-Cabezas et al. 2019. PubMed ID: 30763667). This variant is reported in 0.040% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-117199562-G-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.