ClinVar Genomic variation as it relates to human health

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Benign by Emory. Compund heterozygotes foe this variant and %508del variant were clinically normal, therefore this variant has been classified as benign by Kobayashi et al 1990. Frequency of the variant was higher in individuals with CBAVD (Havasi 2008). Phenotype does not meet reporting criteria.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

The CFTR c.1523T>G; p.Phe508Cys variant (rs74571530) is reported in the literature in individuals affected with monosymptomatic CFTR-related disorders, such as congenital bilateral absence of the vas deferens or pancreatitis, who also carried an additional pathogenic variant on the opposite chromosome (Dork 1997, Havasi 2008, Meschede 1993, Palermo 2016). This variant has also been reported in asymptomatic individuals (Desgeorges 1994, Kobayashi 1990, Macek 1992), although this may be due to reduced penetrance of CFTR-related disorders. This variant is listed in ClinVar (Variation ID: 7126), and is present in the non-Finnish European population with an overall allele frequency of 0.18% (230/125858 alleles) in the Genome Aggregation Database. The phenylalanine at codon 508 is highly conserved, and computational programs (PolyPhen-2, SIFT) predict that this variant is deleterious. Based on available information, this variant is considered mildly pathogenic and not causative for classic cystic fibrosis. References: Desgeorges M et al. A healthy male with compound and double heterozygosities for delta F508, F508C, and M47OV in exon 10 of the cystic fibrosis gene. Am J Hum Genet. 1994 54(2):384-5. Dork T et al. Distinct spectrum of CFTR gene mutations in congenital absence of vas deferens. Hum Genet. 1997 100(3-4):365-77. Havasi V et al. The role of the F508C mutation in congenital bilateral absence of the vas deferens. Genet Med. 2008 10(12):910-4. Kobayashi K et al. Benign missense variations in the cystic fibrosis gene. Am J Hum Genet. 1990 47(4):611-5. Macek M Jr et al. Missense variations in the cystic fibrosis gene: heteroduplex formation in the F508C mutation. Am J Hum Genet. 1992 Nov;51(5):1173-4. Meschede D et al. Compound heterozygosity for the delta F508 and F508C cystic fibrosis transmembrane conductance regulator (CFTR) mutations in a patient with congenital bilateral aplasia of the vas deferens. Am J Hum Genet. 1993 Jul;53(1):292-3. Palermo JJ et al. Genophenotypic Analysis of Pediatric Patients With Acute Recurrent and Chronic Pancreatitis. Pancreas. 2016 Oct;45(9):1347-52.

CFTR: BP2, BS2

ACMG classification criteria: PP3 supporting

The p.F508C variant (also known as c.1523T>G), located in coding exon 11 of the CFTR gene, results from a T to G substitution at nucleotide position 1523. The phenylalanine at codon 508 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was first detected in two healthy individuals who also carried the p.F508del mutation on the other chromosome; thus, the authors suggested a benign classification (Kobayashi K et al. Am. J. Hum. Genet., 1990 Oct;47:611-5). Subsequently, p.F508C was detected with another pathogenic mutation in 3 of 182 individuals with congenital bilateral absence of the vas deferens (CBAVD). This same study also described 5 individuals who were compound heterozygous with another pathogenic mutation in a cohort of 5938 individuals suspected to have CF. However, the frequency of the p.F508C variant in this suspected CF population did not significantly differ from that of their control population (Havasi V et al. Genet. Med., 2008 Dec;10:910-4). Functional studies determined that this substitution does not affect CFTR function, protein folding, or the transport of the protein to the cell membrane, but could affect ion channel function, particularly when co-occurring with another alteration (Raraigh KS et al. Am. J. Hum. Genet., 2018 Jun;102:1062-1077; Du K et al. Nat. Struct. Mol. Biol., 2005 Jan;12:17-25; Cui L et al. J. Physiol. (Lond.), 2006 Apr;572:347-58). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, this variant is unlikely to be causative of classic CF; however, its contribution to the development of a CFTR-related disorder is uncertain. This alteration is thus classified as a variant of unknown significance.