ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.509G>A (p.Arg170His) (rs1800079)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000047174 SCV000075187 uncertain significance Cystic fibrosis 2018-11-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 170 of the CFTR protein (p.Arg170His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs1800079, ExAC 0.07%). This variant has been reported in combination with a pathogenic variant in individuals with congenital absence of the vas deferens (CAVD) (PMID: 21520337, 16617247, 16189704), which suggests it may contribute to disease. However, this variant has also been reported without a clearly pathogenic variant in several individuals with CAVD (PMID: 17329263) or chronic pancreatitis (PMID: 25033378, 16189704, 27171515, 19812525), raising questions about its role in these diseases. ClinVar contains an entry for this variant (Variation ID: 53983). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724146 SCV000230936 uncertain significance not provided 2016-10-19 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000047174 SCV000466504 uncertain significance Cystic fibrosis 2019-04-05 criteria provided, single submitter clinical testing The CFTR c.509G>A (p.Arg170His) missense variant has been reported in at least five studies in which it is found in several individuals with variable but generally milder presentations of CFTR-related disorders. The p.Arg170His variant was found in four individuals with congenital bilateral absence of vas deferens (CBAVD), including three compound heterozygotes and one heterozygote; in one heterozygous individual with cystic fibrosis (CF); and in five heterozygous individuals with pancreatitis (Bishop et al. 2005; Ratbi et al. 2007; Steiner et al. 2011; Krenkova et al. 2013; LaRusch et al. 2014). Two additional individuals with CBAVD reported in the Cystic Fibrosis Mutation Database were compound heterozygous for the p.Arg170His variant and a second well-known pathogenic variant (http://www.genet.sickkids.on.ca/app). The p.Arg170His variant was found in a heterozygous state in two of approximately 1800 total controls from the above studies and is reported at a frequency of 0.0071 in the Ashkenazi Jewish population of the Genome Aggregation Database. Aissat et al. (2013) demonstrated that when the p.Arg170His variant is present, there is a significant increase in exon 5 skipping as compared to that observed in wild type. Recently, however, Salinas et al. (2016) and the CFTR2 database (https://www.cftr2.org/) reported nine compound heterozygous children ascertained by newborn screening who carried the p.Arg170His variant in trans with known disease-causing CFTR variants without a positive sweat chloride test, pancreatic insufficiency or P. aeruginosa colonization, confounding the clinical implications of this variant. Based on the evidence, the p.Arg170His variant is classified as a variant of unknown significance but suspicious for pathogenicity for CFTR-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx RCV000724146 SCV000564865 uncertain significance not provided 2017-10-17 criteria provided, single submitter clinical testing The R170H variant in the CFTR gene has been reported previously in the heterozygous state, and in the presence of a second CFTR variant, in individuals with congenital absence of the vas deferens, pancreatitis, and cystic fibrosis (LaRusch et al., 2014; Steiner et al., 2011; Krenkova et al., 2013). However, California newborn screening data indicates children carrying R170H and a CF-causing pathogenic variant have had a benign clinical course (Salinas et al., 2016). Functional studies showed the R170H variant had normal chloride but no bicarbonate permeability and conductance with WNK1-SPAK activation (LaRusch et al., 2014). The R170H variant is observed in 72/10136 (0.71%) alleles from individuals of Ashkenazi Jewish background, in the ExAC dataset (Lek et al., 2016). The R170H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. We interpret R107H as a variant of uncertain significance. While the R170H variant is not likely to be a CF-causing variant, it is possible this variant may have reduced penetrance in association with CF-related disorders.
Integrated Genetics/Laboratory Corporation of America RCV000178781 SCV000697032 pathogenic Congenital bilateral absence of the vas deferens 2018-08-08 criteria provided, single submitter clinical testing Variant summary: CFTR c.509G>A (p.Arg170His) results in a non-conservative amino acid change located in the ABC transporter type 1 transmembrane domain (IPR011527) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Though 5/5 computational tools predict no significant impact on normal splicing, one publication reported experimental evidence that this variant significantly increased the skipping of exon 5 in vitro, in a minigene construct, compared with the wild type (Aissat_2013). The variant allele was found at a frequency of 0.00051 in 280372 control chromosomes (gnomAD and publications). This frequency is lower than expected for a pathogenic variant in CFTR causing Congenital Bilateral Absence of the Vas Deferens (CBAVD) (0.00051 vs 0.013), allowing no conclusion about variant significance. The variant, c.509G>A, has been reported in the literature and locus specific database (UMD) in compound heterozygosity, in most cases with a CF-causing variant, in multiple CBAVD patients, who had no classic cystic fibrosis (CF) phenotype (Wei_2006, Taulan_2007, Steiner_2011, McGinniss_2005, Ratbi_2007) and in infants (also in combination with a CF-causing variant) who were undergoing newborn screening, and had no CF phenotype (Salinas_2016). In addition, the variant was reported in heterozygosity, i.e. without a second variant, in a few patients diagnosed with idiopathic chronic pancreatitis (ICP) (Bishop_2005, Steiner_2011) or cystic fibrosis (CF) (Alibakhshi_2008, Baker_2011, Krenkova_2012) however, it was also found in several controls (Bombieri_2000, Steiner_2011, Modiano_2005, Pompei_2006). These data indicate that the variant is very likely to be associated with CBAVD, but allow no conclusion about its association with CF. At least one publication reported experimental evidence evaluating an impact on protein function, demonstrating that while the p.Arg170His protein had normal folding, glycosylation and chloride channel activities, it had impaired bicarbonate permeability and conductance (LaRush_2014), which may potentially explain the pathophysiology of CBAVD. Authors suggested that the selective bicarbonate defect in CFTR channel function might affect those organs that utilize CFTR for bicarbonate secretion (e.g. the pancreas, nasal sinus, vas deferens), causing associated symptoms (e.g. increased risk for rhinosinusitis and male infertility), but not typical CF. Five other 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 pathogenic for CBAVD.
Counsyl RCV000047174 SCV000800728 uncertain significance Cystic fibrosis 2017-07-18 criteria provided, single submitter clinical testing
Mendelics RCV000047174 SCV000886352 uncertain significance Cystic fibrosis 2018-11-05 criteria provided, single submitter clinical testing

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