ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.509G>A (p.Arg170His) (rs1800079)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000047174 SCV000075187 uncertain significance Cystic fibrosis 2019-12-15 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 ( 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 ( 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000178781 SCV000697032 uncertain significance not specified 2020-07-13 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. Four of four computational tools predict no significant impact on normal splicing, although at-least one publication reported experimental evidence that this variant increased the skipping of exon 5 in vitro, in a minigene construct, compared with the wild type (Aissat_2013). However, the exact physiological consequences of this finding are not clearly established. The variant allele was found at a frequency of 0.00051 in 254598 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Congenital Bilateral Absence of the Vas Deferens (0.0051 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 may be associated with CBAVD, but allow no conclusion about its association with classic CF. Several publications report experimental evidence evaluating an impact on protein function. One study demonstrated that while the p.Arg170His protein had normal folding, glycosylation, chloride channel, bicarbonate permeability and bicarbonate conductance activities, it had impaired bicarbonate permeability in the setting of WNK1, and SPAK co-expression at low chloride ion levels (LaRusch_2014). 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. Another publication assessed protein function in vitro by evaluating CFTR mutants that were stably expressed in the genome of a human airway cell line devoid of endogenous CFTR expression (CFBE41o- cells): the authors of this study reported that cells expressing the variant protein functioned at levels similar to wild-type (Raraigh_2018). Ten other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. They have cited the variant as uncertain significance (n=8), likely pathogenic (n=1), and pathogenic (n=1), citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance for all possible phenotypes associated with CF, CFTR-related disorders, and 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
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000724146 SCV001134147 uncertain significance not provided 2019-07-12 criteria provided, single submitter clinical testing
CFTR-France RCV001009504 SCV001169599 pathogenic CFTR-related disorders 2018-01-29 criteria provided, single submitter curation
Ambry Genetics RCV001023534 SCV001185433 uncertain significance Inborn genetic diseases 2020-06-26 criteria provided, single submitter clinical testing The p.R170H variant (also known as c.509G>A), located in coding exon 5 of the CFTR gene, results from a G to A substitution at nucleotide position 509. The arginine at codon 170 is replaced by histidine, an amino acid with highly similar properties. In one study, this variant, in conjunction with a CFTR pathogenic mutation (phase unknown), was detected in a male with congenital bilateral absence of the vas deferens (CBAVD) (Wei S et al. Genet. Med., 2006 Apr;8:255-8). Another study described this variant in conjunction with a pathogenic mutation (phase unknown) in a male with pancreatitis and CBAVD (McGinniss MJ et al. Hum. Genet., 2005 Dec;118:331-8). An in vitro study reported cell lines expressing this variant secrete chloride but do not secrete bicarbonate, which is needed for normal function in the pancreas and male reproductive tract. This result suggests that this variant may contribute to chronic pancreatitis rather than classic cystic fibrosis (CF) (LaRusch J et al. PLoS Genet., 2014 Jul;10:e1004376). Consistent with this finding, human airway cells (CFBE) expressing p.R170H demonstrated 150% of wild type CFTR function (Raraigh KS et al. Am. J. Hum. Genet., 2018 Jun;102:1062-1077). In a retrospective analysis of a cohort of newborns with elevated IRT on newborn screening, the p.R170H alteration was identified in 9 individuals with a CF-causing mutation confirmed in trans. In these individuals, sweat chloride levels were normal and none of the evaluated individuals were pancreatic insufficient or had persistent Pseudonomas aeruginosa colonization (Salinas DB et al. PLoS ONE, 2016 May;11:e0155624). 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, this variant is unlikely to be causative of classic CF; however, it may contribute to the development of a CFTR-related disorder.
Johns Hopkins Genomics, Johns Hopkins University RCV000047174 SCV001425313 likely benign Cystic fibrosis 2020-03-09 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001289594 SCV001477556 pathogenic none provided 2020-07-13 criteria provided, single submitter clinical testing The CFTR c.509G>A; p.Arg170His variant (rs1800079) is reported in the literature in the compound heterozygous state in multiple individuals affected with chronic pancreatitis or other CFTR-related diseases (Gallati 2009, LaRusch 2014, Palermo 2016, Steiner 2011, Wei 2006). Functional analyses of the variant show a slight increase in exon 5 skipping (Aissat 2013), but mature protein expression levels and chloride transport activity similar to wildtype (LaRusch 2014). However, the variant protein exhibits impaired bicarbonate transport, which is also observed for other CFTR variants enriched in pancreatitis patients (LaRusch 2014). This variant is reported in ClinVar (Variation ID: 53983), and is found in the Ashkenazi Jewish population with an allele frequency of 0.72% (75/10358 alleles) in the Genome Aggregation Database. The arginine at residue 170 is highly conserved, and computational algorithms (Mutation Taster, PolyPhen-2, SIFT) predict that this variant is deleterious. Additionally, other variants at this codon (c.508C>T; p.Arg170Cys, c.508C>G; p.Arg170Gly) have been reported in individuals with CFTR-related diseases (Sharma 2014, see link to cystic fibrosis mutation database). Based on available information, the p.Arg170His variant is considered to be mildly pathogenic. References: Link to cystic fibrosis mutation database: Aissat A et al. Combined computational-experimental analyses of CFTR exon strength uncover predictability of exon-skipping level. Hum Mutat. 2013 34(6):873-81. Gallati S et al. Cystic fibrosis transmembrane conductance regulator mutations in azoospermic and oligospermic men and their partners. Reprod Biomed Online. 2009 19(5):685-94. LaRusch J et al. Mechanisms of CFTR functional variants that impair regulated bicarbonate permeation and increase risk for pancreatitis but not for cystic fibrosis. PLoS Genet. 2014 10(7):e1004376. 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. Steiner B et al. Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. Hum Mutat. 2011 32(8):912-20. Wei S et al. Cystic Fibrosis testing among Arab-Americans. Genet Med. 2006 8(4):255-8.
Mayo Clinic Laboratories, Mayo Clinic RCV000724146 SCV001715941 uncertain significance not provided 2021-03-26 criteria provided, single submitter clinical testing
Molecular Genetics Laboratory,BC Children's and BC Women's Hospitals RCV001009504 SCV001338826 likely pathogenic CFTR-related disorders 2019-11-28 no assertion criteria provided clinical testing
Natera, Inc. RCV000047174 SCV001454021 uncertain significance Cystic fibrosis 2020-09-16 no assertion criteria provided clinical testing

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