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

gnomAD frequency: 0.00045  dbSNP: rs1800079

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000047174	SCV000075187	likely benign	Cystic fibrosis	2024-01-30	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000724146	SCV000230936	uncertain significance	not provided	2016-10-19	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, 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	2023-10-27	criteria provided, single submitter	clinical testing	Described as a bicarbonate defective allele in published functional studies: decrease of CFTR bicarbonate conductance and altered bicarbonate permeation of the CFTR channel while not affecting the chloride channel (PMID: 25033378, 29805046); Observed with a pathogenic CFTR variant, phase unknown, in published literature in individuals with cystic fibrosis and/or congenital absence of the vas deferens but also in unaffected individuals (PMID: 27728908, 27214204, 16189704, 21520337, 16617247, 17448246); Observed in published literature in individuals with pancreatitis (PMID: 21520337, 16189704, 25033378); In silico analysis supports that this missense variant does not alter protein structure/function; Classified as a non CF-causing variant in a well-curated database (CFTR2); This variant is associated with the following publications: (PMID: 27171515, 26847993, 28502372, 17329263, 28456595, 20021716, 29805046, 23276700, 27214204, 28194692, 27104957, 10746558, 16193325, 16244288, 17662673, 20059485, 21388895, 26708955, 27728908, 18716917, 29589582, 28465863, 15536480, 16251901, 26277102, 23420618, 25033378, 21520337, 16617247, 16189704, 17448246, 32143663, 34426522, 34525262, 34860163, 34405919, 34996830, 32508047, 35753512)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000178781	SCV000697032	uncertain significance	not specified	2023-10-30	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. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00051 in 254598 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Congenital Bilateral Absence Of The Vas Deferens (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). The variant was also reported in a CF patient with another pathogenic variant (Combret_2021), however, in another CF-case a co-occurrence with a homozygous pathogenic variant has been reported (CFTR c.988G>T, p.Gly330Ter; in Lascano-Vaca_2020), providing supporting evidence for a non-causative role. 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), but, 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. Publications also reported 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 pancreatitis, rhinosinusitis and male infertility), but not typical CF. Another publication assessed chloride channel function in vitro by evaluating CFTR mutants that were stably expressed in the genome of a human airway cell line devoid of endogenous CFTR, and found that cells expressing the variant protein had similar chloride channel function to the wild-type (Raraigh_2018). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments (pathogenic n=2, likely pathogenic n=1, VUS n=14, likely benign n=2). Based on the conflicting evidence outlined above, the variant was classified as uncertain significance.
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	2023-08-10	criteria provided, single submitter	clinical testing	The CFTR c.509G>A (p.Arg170His) variant has been reported in the published literature along with other CF variants in individuals with Cystic Fibrosis (PMID: 32143663 (2020), 33577586 (2021), 23276700 (2013), 21520337 (2011)). This variant is also reported in individuals with Cystic Fibrosis Related Disorder (CFRD) including CBAVD (congenital absence of the vas deferens) (PMID: 17329263 (2007), 16189704 (2005)), pancreatitis (PMID: 27171515 (2016), 25033378 (2014), 16189704 (2005)) and azoospermia (PMID: 20021716 (2009)). A functional study reported that this variant demonstrated chloride conductance similar to wild type CFTR protein (PMID: 29805046 (2018)). Another functional study found normal chloride function but abnormal bicarbonate permeability and conductance (PMID: 25033378 (2014)). The frequency of this variant in the general population, 0.0072 (75/10358 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
CFTR-France	RCV001009504	SCV001169599	pathogenic	CFTR-related disorders	2018-01-29	criteria provided, single submitter	curation
Ambry Genetics	RCV000047174	SCV001185433	uncertain significance	Cystic fibrosis	2023-01-04	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. This alteration was identified in 9 children with a CF-causing mutation confirmed in trans; none of the children had elevated sweat chloride levels, pancreatic insufficiency, or Pseudonomas aeruginosa colonization (Salinas DB et al. PLoS One, 2016 May;11:e0155624). However, this variant has also been detected in conjunction with a CFTR pathogenic mutation in multiple individuals with intermediate sweat chloride levels and/or CFTR-related disorders, including chronic pancreatitis and congenital bilateral absence of the vas deferens (Wei S et al. Genet. Med., 2006 Apr;8:255-8; McGinniss MJ et al. Hum Genet, 2005 Dec;118:331-8; Taulan M et al. BMC Med Genet, 2007 Apr;8:22; Ambry internal data). In an in vitro study, this variant demonstrated 150% chloride channel function, compared to wild type (Raraigh KS et al. Am J Hum Genet, 2018 06;102:1062-1077). In a separate study, the variant showed normal chloride function, but reduced bicarbonate permeability and conductance (LaRusch J et al. PLoS Genet, 2014 Jul;10:e1004376). 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 cystic fibrosis; however, its contribution to the development of a CFTR-related disorder is uncertain. This alteration is thus classified as a variant of unknown significance.
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	RCV000724146	SCV001477556	pathogenic	not provided	2023-09-14	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 disorders (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 analyses predict that this variant is deleterious (REVEL: 0.829). 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, while the p.Arg170His variant is not predicted to result in cystic fibrosis, it is considered to be mildly pathogenic for CFTR-related disorders. References: Link to cystic fibrosis mutation database: http://genet.sickkids.on.ca/cftr/Home.html 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. PMID: 23420618. 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. PMID: 20021716. 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. PMID: 25033378. Palermo JJ et al. Genophenotypic Analysis of Pediatric Patients With Acute Recurrent and Chronic Pancreatitis. Pancreas. 2016 Oct;45(9):1347-52. PMID: 27171515. 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. PMID: 24958810. 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. PMID: 21520337. Wei S et al. Cystic Fibrosis testing among Arab-Americans. Genet Med. 2006 8(4):255-8. PMID: 16617247.
Mayo Clinic Laboratories, Mayo Clinic	RCV000724146	SCV001715941	uncertain significance	not provided	2022-09-20	criteria provided, single submitter	clinical testing	PP3, PM2
Genome-Nilou Lab	RCV000047174	SCV001822007	uncertain significance	Cystic fibrosis	2021-07-22	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000047174	SCV002507362	uncertain significance	Cystic fibrosis	2020-10-22	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV001802207	SCV002529737	uncertain significance	Hereditary pancreatitis	2021-12-08	criteria provided, single submitter	curation
Institute of Human Genetics, University of Leipzig Medical Center	RCV000047174	SCV002574016	uncertain significance	Cystic fibrosis	2023-08-03	criteria provided, single submitter	curation	This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). The patient has not been seen or tested by our laboratory. Clinical diagnosis was documented in the Registry. Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PM3, PS3_SUP, PM5_STR, PP3, BP2, BS3_SUP
Genetics and Molecular Pathology, SA Pathology	RCV000047174	SCV002761428	uncertain significance	Cystic fibrosis	2020-02-18	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV003322594	SCV004027736	likely pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-07-18	criteria provided, single submitter	clinical testing	Criteria applied: PM5_STR,PM3,PS3_SUP,PP3,BP2
PreventionGenetics, part of Exact Sciences	RCV003430655	SCV004116866	uncertain significance	CFTR-related condition	2023-12-09	criteria provided, single submitter	clinical testing	The CFTR c.509G>A variant is predicted to result in the amino acid substitution p.Arg170His. This variant has been reported in association with cystic fibrosis (Alibakhshi et al. 2008. PubMed ID: 17662673; Baker et al. 2011. PubMed ID: 21388895; Křenková et al. 2013. PubMed ID: 23276700; Prontera et al. 2016. PubMed ID: 27728908) and CFTR-related disorders such as congenital bilateral absence of the vas deferens and/or chronic pancreatitis (McGinniss et al. 2005. PubMed ID: 16189704; Wei et al. 2006. PubMed ID: 16617247; Ratbi et al. 2007. PubMed ID: 17329263; Taulan et al. 2007. PubMed ID: 17448246; de Cid et al. 2010. PubMed ID: 19812525; Steiner et al. 2011. PubMed ID: 21520337; LaRusch et al. 2014. PubMed ID: 25033378; Palermo et al. 2016. PubMed ID: 27171515). However, this variant has also been reported in unaffected control subjects (Steiner et al. 2011. PubMed ID: 21520337) and patients carrying a second CF-causing variant with a benign clinical course, or features that were not consistent with a diagnosis of cystic fibrosis (Salinas et al. 2016. PubMed ID: 27214204; https://cftr2.org/mutation/general/R170H/). Functional studies indicate that the p.Arg170His variant reduces bicarbonate conductance in vitro, but does not impact protein folding, glycosylation, or chloride channel activities (LaRusch et al. 2014. PubMed ID: 25033378). This variant is reported in 0.72% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. While it is possible that the c.509G>A (p.Arg170His) variant may contribute to CFTR-related disorders with incomplete penetrance, at this time we interpret it to be a variant of uncertain significance due to conflicting genetic and functional data.
CeGaT Center for Human Genetics Tuebingen	RCV000724146	SCV004158945	uncertain significance	not provided	2022-06-01	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
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001009504	SCV002507446	uncertain significance	CFTR-related disorders	2020-10-22	no assertion criteria provided	clinical testing