ClinVar Genomic variation as it relates to human health

The CFTR c.508C>T; p.Arg170Cys variant (rs578029902) is reported in the literature in the heterozygous state individuals affected with CFTR-related disorders (Casals 2004, Coste 2004, de Cid 2010, Sharma 2014), and in one individual with alcohol-related pancreatitis who also carries a common pathogenic CFTR variant (Bernardino 2003). This variant is reported in ClinVar (Variation ID: 455782), and is found in the general population with an overall allele frequency of 0.005% (13/250410 alleles) in the Genome Aggregation Database. The arginine at residue 170 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. Additionally, other variants at this codon (c.509G>A; p.Arg170His, c.508C>G; p.Arg170Gly) have been reported in individuals with CFTR-related diseases (Palermo 2016, see link to cystic fibrosis mutation database). Based on available information, the p.Arg170Cys variant is not expected to cause classic cystic fibrosis, however, it remains uncertain whether it may contribute to the clinical phenotype in individuals with milder CFTR-related disease (e.g., an isolated presentation of pancreatitis, congenital bilateral absence of the vas deferens, or mild lung disease). References: Link to cystic fibrosis mutation database: http://genet.sickkids.on.ca/cftr/Home.html Bernardino AL et al. CFTR, PRSS1 and SPINK1 mutations in the development of pancreatitis in Brazilian patients. JOP. 2003 Sep;4(5):169-77. Casals T et al. Different CFTR mutational spectrum in alcoholic and idiopathic chronic pancreatitis? Pancreas. 2004 May;28(4):374-9. Coste A et al. Atypical sinusitis in adults must lead to looking for cystic fibrosis and primary ciliary dyskinesia. Laryngoscope. 2004 May;114(5):839-43. de Cid R et al. Independent contribution of common CFTR variants to chronic pancreatitis. Pancreas. 2010 Mar;39(2):209-15. Palermo JJ et al. Genophenotypic Analysis of Pediatric Patients With Acute Recurrent and Chronic Pancreatitis. Pancreas. 2016 Oct;45(9):1347-52. Sharma H et al. Heterogeneous spectrum of mutations in CFTR gene from Indian patients with congenital absence of the vas deferens and their association with cystic fibrosis genetic modifiers. Mol Hum Reprod. 2014 Sep;20(9):827-35.

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 170 of the CFTR protein (p.Arg170Cys). This variant is present in population databases (rs578029902, gnomAD 0.02%). This missense change has been observed in individual(s) with alcohol-related pancreatitis and congenital absence of the vas deferens (PMID: 14526128, 15097853, 15126740, 24958810). ClinVar contains an entry for this variant (Variation ID: 455782). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Arg170 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been observed in individuals with CFTR-related conditions (PMID: 16189704, 16617247, 21520337), which suggests that this may be a clinically significant amino acid residue. 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.

Variant summary: CFTR c.508C>T (p.Arg170Cys) results in a non-conservative amino acid change located in the first 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 5.6e-05 in 252182 control chromosomes (gnomAD and publication data). This frequency is not higher than the estimated maximum expected for a pathogenic variant in CFTR causing Cystic Fibrosis (5.6e-05 vs 0.013), allowing no conclusion about variant significance. The variant, c.508C>T, has been reported in compound heterozygous state in at least 2 patients affected with cystic fibrosis (Soltysova_2017, Erdogan_2021), and in heterozygous state (or without a 2nd variant specified) in individuals affected with suspected CF, alcohol-related pancreatitis, congenital absence of the vas deferens (Bernardino_2003, Casals_2004, Sharma_2014, Pagin_2016), but was also found in controls (Le Marechal_2001, Modiano_2005). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, two different missense changes affecting the same amino acid (R170E and R170G) showed defect in transport to the Golgi complex (PMID: 33771570). The following publications have been ascertained in the context of this evaluation (PMID: 14526128, 15097853, 15126740, 19812525, 15536480, 16251901, 24958810, 11379874, 26900683, 28544683, 30592194, 34860163, 33771570). Eight other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, mostly without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

The p.R170C variant (also known as c.508C>T), located in coding exon 5 of the CFTR gene, results from a C to T substitution at nucleotide position 508. The arginine at codon 170 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was detected in an individual with alcohol related pancreatitis in conjunction with p.F508del (Bernardino AL et al. JOP, 2003 Sep;4:169-77). This variant was also identified in one individual with alcohol related pancreatitis and infertility and one individual diagnosed with congenital absence of the vas deferens (Casals T et al. Pancreas, 2004 May;28:374-9; Sharma H et al. Mol. Hum. Reprod., 2014 Sep;20:827-35). In addition, this variant was identified in a control individual (Le Marechal et al. Hum Genet. 2001 Apr;108(4):290-8). This alteration was also identified in an individual diagnosed with cystic fibrosis however further details were not provided (Erdoan M et al. Balkan Med J, 2021 Nov;38:357-364). 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, the clinical significance of this alteration remains unclear.

This CFTR missense variant has been identified in individuals features of cystic fibrosis but not a classic cystic fibrosis phenotype. This variant (rs578029902) is rare (<0.1%) in a large population dataset (gnomADv2.1.1: 13/ 250410 total alleles; 0.005%; no homozygotes) and has been reported in ClinVar (Variation ID: 455782). Two bioinformatic tools queried predict that this substitution would be damaging and the arginine residue at this position is evolutionarily conserved across most species assessed. We consider the clinical significance of CFTR c.508C>T to be uncertain at this time.

The missense variant c.508C>T(p.Arg170Cys) in CFTR (NM_000235.4) has been submitted to ClinVar as a Variant of Uncertain Significance. This variant was detected in an individual with alcohol related pancreatitis in conjunction with p.F508del (Bernardino AL et al., 2003). This variant was also found in one individual with alcohol related pancreatitis and infertility and one individual with congenital absence of the vas deferens (Casals T et al., 2004; Sharma H et al., 2014). This variant is reported with the allele frequency of 0.005% and 0.02% in the gnomad and 1000 genome databases respectively. The amino acid Arginine at position 170 is changed to a Cysteine changing protein sequence and it might alter its composition and physico-chemical properties. The p.Arg170Cys missense variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. For these reasons, this variant has been classified as Uncertain Significance.