ClinVar

Description

This sequence change in CFTR is predicted to replace arginine with histidine at codon 170, p.(Arg170His). The arginine residue is highly conserved (92/95 vertebrates, UCSC), and is located in exon 5 within the ABC transporter transmembrane region. There is a small physicochemical difference between arginine and histidine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.03% (42/128,708 alleles) in the European (non-Finnish) population, which is consistent with autosomal recessive cystic fibrosis (CF), but higher than expected for autosomal dominant hereditary pancreatitis. This variant has been observed in nine compound heterozygous children along with a known pathogenic CFTR variant who were detected by newborn screening, with no objective features of cystic fibrosis as defined by pancreatic insufficiency, positive chloride sweat test or lung pseudomonas colonisation (PMID: 27214204). However, this variant has been reported in at least sixteen heterozygous probands (both heterozygotes and compound heterozygotes with a known pathogenic CFTR variant- phase unknown in all but two individuals of the latter group where it is in trans) meeting the criteria for a CFTR-related disorder other than cystic fibrosis, including recurrent acute pancreatitis, chronic pancreatitis or congenital bilateral absence of vas deferens (CBAVD; PMID: 16193325, 17329263, 16189704, 16617247; CFTR France variant database, https://cftr.iurc.montp.inserm.fr/cftr/). The CFTR2 variant database (https://cftr2.org/) records eleven alleles with this variant amongst 89,052 individuals, with 33% of compound heterozygote individuals with this variant and a known pathogenic CFTR variant recorded as having pancreatic insufficiency. The prevalence of the variant in affected individuals with chronic pancreatitis is significantly increased compared with the prevalence in gnomAD controls (OR = 2.6798, 95% CI 1.0594 - 6.7784), using the aggregated case figures from a meta-analysis of six studies with this variant (PMID: 36264955). This variant has been observed with the pathogenic variant (c.3846G>A, p.Trp1282Ter; ClinVar: VCV000007129.90) in an individual diagnosed with CF on a positive chloride sweat test, although the patient had relatively normal pulmonary function and performance status compared to other cystic fibrosis patients in this cohort (PMID: 33577586). The phase of the variants is unknown. Other reports exist of this variant detected in at least five individuals diagnosed with CF; however, it is unclear in these cases whether different variants may be responsible (e.g. PMID: 32143663, 21388895, 17662673), and/or the phenotype information is missing or incomplete (e.g. PMID: 27728908, 23276700). Western blot and patch clamp in vitro experiments using HEK 293T cells transfected with variant protein demonstrated normal protein expression and glycosylation along with chloride permeability, but reduced bicarbonate permeability/conductance in the presence of WNK1/SPAK, which models the bicarbonate-dependent pathophysiology of CFTR variants in the pancreas, sinuses and male reproductive tract (PMID: 25033378). This, along with other data showing normal chloride conductance in human epithelial cell lines expressing mutant protein constructs (PMID: 29805046) indicates that the impact of the variant on protein function is limited to bicarbonate conductance in specific organs (including the pancreas, but excluding the lungs). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE (VUS). Following criteria are met: PP3, PS3_Supporting, PS4_Supporting.