ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.350G>A (p.Arg117His)

dbSNP: rs78655421
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Total submissions: 41
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
American College of Medical Genetics and Genomics (ACMG) RCV000007528 SCV000071404 pathogenic Cystic fibrosis 2004-03-03 practice guideline curation Converted during submission to Pathogenic.
PharmGKB RCV000417156 SCV000494724 drug response ivacaftor response - Efficacy 2021-03-24 reviewed by expert panel curation PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance.
Invitae RCV000007528 SCV000074930 uncertain significance Cystic fibrosis 2024-01-31 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 117 of the CFTR protein (p.Arg117His). This variant is present in population databases (rs78655421, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. This missense variant (also known as R117H) frequently occurs on the same chromosome as a pathogenic CFTR allele known as IVS8-5T (PMID: 7506096, 11491164). The 5T refers to a polymorphic region in the intron preceding the acceptor splice site for exon 10 (formerly called exon 9). The 5T allele has been demonstrated to result in aberrant mRNA splicing and a non-functional protein, while more common 7T and 9T alleles do not impact splicing and are considered benign (PMID: 7691356, 7684641, 10556281, 14685937, 21658649). Importantly, when R117H is on the same chromosome as the 5T, it may increase the severity of CFTR-related symptoms (PMID: 7506096, 11491164). When on the same chromosome as a 7T or 9T, the R117H variant is not typically associated with cystic fibrosis but may contribute to CFTR-related conditions (PMID: 21507732, 7506096, 23974870). The R117H and T7 (R117H-T7) allele has been reported to be homozygous in a male with congenital absence of vas deferens (CAVD) (PMID: 21507732). This male also had slightly above normal sweat chloride levels (34 mmol/L) but was otherwise asymptomatic for CFTR-related symptoms. In addition, 81 males with R117H-T7 and Phe508del on opposite alleles have been observed to have CAVD, although it has been estimated that only a small percentage (3%) of males in the population with this genotype are affected (PMID: 19880712). ClinVar contains an entry for this variant (Variation ID: 7109). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 80%. The experimental evidence for the R117H-T7 is conflicting. In a heterologous model system, this missense change decreased CFTR activity by ~20-30% (PMID: 11242048), while in airway epithelium cells taken from two individuals homozygous for R117H-T7, chloride conductance levels were normal (PMID: 21507732). In summary, this R117H missense variant may modify disease severity when it occurs on the same chromosome as a 5T allele. When present on the same chromosome as a 7T or 9T allele, the R117H variant does not typically contribute to cystic fibrosis but may contribute to CFTR-related conditions. However, much of the functional and clinical data for the R117H-T7 allele is conflicting. Until this can be resolved, the R117H missense change has been classified as a Variant of Uncertain Significance.
Courtagen Diagnostics Laboratory, Courtagen Life Sciences RCV000007528 SCV000236522 pathogenic Cystic fibrosis 2014-04-23 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics RCV000078997 SCV000281214 pathogenic not provided 2015-02-11 criteria provided, single submitter clinical testing
GeneDx RCV000078997 SCV000329245 pathogenic not provided 2018-05-07 criteria provided, single submitter clinical testing The R117H variant in the CFTR gene has been reported multiple times previously as a common variant in the CFTR gene (Moskowitz et al., 2008). R117H is a class IV variant which results in defective protein conductance but allows for some residual CFTR function (De Boeck et al., 2014). The severity of disease in individuals with one or two R117H pathogenic variants depends on the presence of a variation in the intron 8 poly T tract and the length of the TG tract in cis configuration with the R117H variant (Moskowitz et al., 2008). A longer TG tract in association with a shorter poly T tract has the strongest adverse effect on intron 8 splicing and are associated with more severe disease (Moskowitz et al., 2008). Individuals with a CFTR pathogenic variant in trans with the R117H variant and 5T variant usually develop the lung disease of CF, but individuals with R117H and the 7T variant or the 9T variant have a highly variable phenotype ranging from clinically asymptomatic to congenital absence of the vas deferens (CAVD) and/or non-classic cystic fibrosis (Moskowitz et al., 2008). Given the available information, we interpret R117H as a pathogenic variant.
Eurofins Ntd Llc (ga) RCV000078997 SCV000330915 pathogenic not provided 2017-05-15 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000007528 SCV000584076 likely pathogenic Cystic fibrosis 2014-11-04 criteria provided, single submitter research
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000078997 SCV000602967 pathogenic not provided 2023-11-13 criteria provided, single submitter clinical testing The CFTR c.350G>A; p.Arg117His (R117H) variant (rs78655421) is reported in gene-specific databases (CFTR2 Database, ABCC7 Database and references therein) and ClinVar (Variation ID: 7109). Functional analyses show that p.Arg117His protein has reduced conductance and a decreased occupancy in the open state (LaRusch 2014, Van Goor 2014, Yu 2016), and this variant is found in the general population at an overall allele frequency of 0.1% (398/276670 alleles, 1 homozygote) in the Genome Aggregation Database. The p.Arg117His variant is associated with two haplotypes of differing phenotypes when identified with a pathogenic variant on the opposite chromosome. When p.Arg117H is on the same chromosome as the 5T variant in IVS 8, this complex variant is considered pathogenic for cystic fibrosis, but in the absence of 5T, p.Arg117His alone is considered mildly pathogenic and associated with CFTR-related disorders, such as an isolated presentation of congenital bilateral absence of the vas deferens or pancreatitis or mild lung disease (Kiesewetter 1993, Raraigh 2022). References: CFTR2 database: http://cftr2.org/ ABCC7 database: http://abcmutations.hegelab.org/mutationDetails?id=4117 Kiesewetter S et al. A mutation in CFTR produces different phenotypes depending on chromosomal background. Nat Genet. 1993 Nov;5(3):274-8. PMID: 7506096. 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 Jul 17;10(7):e1004376. PMID: 25033378. Raraigh KS et al. Complete CFTR gene sequencing in 5,058 individuals with cystic fibrosis informs variant-specific treatment. J Cyst Fibros. 2022 May;21(3):463-470. PMID: 34782259. Van Goor F et al. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros. 2014 Jan;13(1):29-36. PMID: 23891399. Yu YC et al. On the mechanism of gating defects caused by the R117H mutation in cystic fibrosis transmembrane conductance regulator. J Physiol. 2016 Jun 15;594(12):3227-44. PMID: 26846474.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000007528 SCV000696973 pathogenic Cystic fibrosis 2016-04-11 criteria provided, single submitter clinical testing Variant summary: The variant of interest causes a missense change involving a conserved nucleotide with 5/5 in silico programs predicting a "deleterious" outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 185/120360 (1/650), which does not exceed the predicted maximum expected allele frequency for a pathogenic CFTR variant of 1/100. The variant of interest has been reported in multiple affected individuals via publications and databases that indicate that the variant of interest is a common disease variant with varying severity dependent on additional CFTR variants in cis and trans. Functional studies indicate that the variant of interest impedes wild type function. In addition, multiple reputable clinical laboratories cite the variant with a classification of "pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Pathogenic.
Mendelics RCV000007528 SCV000886267 pathogenic Cystic fibrosis 2018-11-05 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000078997 SCV000888088 pathogenic not provided 2020-01-09 criteria provided, single submitter clinical testing The c.350G>A (p.Arg117His) CFTR pathogenic variant causes the synthesis of a partially functional CFTR protein and is associated with variable expressivity. When this variant occurs on the same chromosome (in cis) with the 7T or 9T polymorphism in intron 9 and with another CFTR pathogenic variant associated with cystic fibrosis (CF) on the opposite chromosome (in trans), it is associated with a variable phenotype. The variable phenotype ranges from asymptomatic to CFTR-related disorders, such as congenital bilateral absence of the vas deferens (CBAVD) in males. However, if the c.350G>A (p.Arg117His) CFTR pathogenic variant occurs in cis with the 5T polymorphism in intron 9 and with a CF pathogenic variant in trans, it is associated with CF (PMID: 32404922 (2020)).
Fulgent Genetics, Fulgent Genetics RCV000763151 SCV000893738 pathogenic Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation 2022-04-13 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000007528 SCV000916176 pathogenic Cystic fibrosis 2017-04-27 criteria provided, single submitter clinical testing The CFTR c.350G>A (p.Arg117His) variant is included within the American College of Medical Genetics and Genomics (ACMG) recommended carrier screening panel for cystic fibrosis (Grody et al. 2001). There are multiple clinical implications for the p.Arg117His variant that are dependent on the length of the intron 8 polythymidine tract (polyT) region within the CFTR gene. Kiesewetter et al. (1993) and Massie et al. (2001) assessed the influence of the intron-8 polythymidine sequence (IVS8) on the relationship between the genotype and phenotype of individuals with the p.Arg117His variant. They found that when the p.Arg117His variant was found in cis with five thymidines (5T), and in trans to a pathogenic CF variant, the individual was most commonly affected with classic CF. When the p.Arg117His variant was identified in cis with seven thymidines (7T) and in trans to a pathogenic CF variant, male individuals were often affected with congenital absence of the vas deferens (CAVD), and males and females often presented with a milder variation of CF. In the CFTR2 database, the variant was found in 793 CF patients (808 alleles) and was classified as a mutation of varying clinical consequence (Sosnay et al. 2013). The p.Arg117His variant is reported at a frequency of 0.00256 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the collective evidence, the p.Arg117His variant is classified as pathogenic for CFTR-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000826137 SCV000967658 pathogenic Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation 2018-10-24 criteria provided, single submitter clinical testing The p.Arg117His variant in the CFTR gene is an established variant for cystic fi brosis (CF) that is recommended for by the American College of Medical Genetics (ACMG) for inclusion on the CF population carrier screening panel (Watson 2004, Moskowitz 2008, Castellani 2008). Functional studies have shown that the p.Arg11 7His variant results in defective protein conductance but retains some residual CFTR function (De Boek 2014). As a result, this variant has been classified as a class IV variant. The severity of lung disease in individuals that are compound heterozygous or homozygous for p.Arg117His variant is contingent on the presenc e of a variation in the poly T/poly TG tract of intron 8 that is in cis (same ch romosome copy) with p.Arg117His. A shorter poly T tract together with a longer T G tract results in the strongest aberrant impact to intron 8 splicing and theref ore associated with more severe disease (Moskowitz 2008). Therefore, individuals with a pathogenic CF variant on one chromosome copy and a 5T variant in cis wit h the p.Arg117His variant on the other chromosome copy usually develop CF-relate d lung disease. In contrast, those with p.Arg117His variant in cis with 7T or 9T variant have a highly variable phenotype that can range from clinically asympto matic to congenital absence of the vas deferens (CAVD) in males and/or non-class ic CF (Kieswetter 1993, Massie 2001). In summary, this variant is classified as pathogenic for CF and related disorders in an autosomal recessive manner. ACMG/A MP criteria applied: PM3_VeryStrong, PS3_Moderate.
Baylor Genetics RCV000826137 SCV001163473 pathogenic Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation criteria provided, single submitter clinical testing
CFTR-France RCV001009478 SCV001169573 pathogenic CFTR-related disorder 2018-01-29 criteria provided, single submitter curation
Ambry Genetics RCV000007528 SCV001181971 pathogenic Cystic fibrosis 2021-10-07 criteria provided, single submitter clinical testing The p.R117H pathogenic mutation (also known as c.350G>A), located in coding exon 4 of the CFTR gene, results from a G to A substitution at nucleotide position 350. The arginine at codon 117 is replaced by histidine, an amino acid with highly similar properties. The penetrance of the p.R117H mutation is modified by the poly-thymidine tract in CFTR intron 9; decreasing length of the poly-thymidine tract correlates with an increased risk for cystic fibrosis phenotype. When p.R117H is on the same chromosome as 5T (in cis) it is a disease causing mutation; when in cis with 7T, the allele acts as a variant of varying clinical consequence (VVCC) (Sosnay PR et al. Nat. Genet. 2013 Oct; 45(10):1160-7; Sosnay PR et al. Pediatr. Clin. North Am. 2016 Aug;63(4):585-98). In a study of 179 individuals who were compound heterozygous for p.R117H and another pathogenic CFTR mutation, 172 had poly-thymidine variant results documented, with the majority being 7T and only five individuals carrying the 5T allele. Clinical data were available for 166 individuals and diagnoses included: isolated CBAVD (83 individuals), CFTR-related disorder with mild or absent pulmonary disease (67 individuals), late-onset marked pulmonary disease (4 individuals), and asymptomatic (12 individuals) (Thauvin-Robinet C et al. J. Med. Genet., 2013 Apr;50:220-7). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc. RCV000007528 SCV001193802 pathogenic Cystic fibrosis 2019-10-18 criteria provided, single submitter clinical testing NM_000492.3(CFTR):c.350G>A(R117H) is classified as pathogenic in the context of cystic fibrosis. Please note that the R117H mutation is associated with a broad spectrum of disease, ranging from clinically asymptomatic to CAVD/non-classic cystic fibrosis. Individuals with R117H should have testing for the poly-T tract (5T) to determine accurate risk. Individuals with R117H and 5T in cis are at highest risk for CF symptoms. In the absence of the 5T haplotype, the R117H mutation is unlikely to produce significant symptoms of cystic fibrosis. The R117H mutation in combination with another disease causing mutation may result in borderline or elevated sweat chloride and mild clinical symptoms of CF, including male infertility. Sources used for classification include PMID 23974870 and 15371902. In summary, classification of NM_000492.3(CFTR):c.350G>A(R117H) is based on the following criteria: high frequency variant with variable penetrance and variable severity dependent on the presence of other variants in the gene. Please note: this variant was assessed in the context of healthy population screening.
CeGaT Center for Human Genetics Tuebingen RCV000078997 SCV001250499 pathogenic not provided 2024-04-01 criteria provided, single submitter clinical testing CFTR: PM3:Very Strong, PM5, PM2:Supporting, PS3:Supporting
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000078997 SCV001251861 pathogenic not provided 2020-05-03 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000078997 SCV001446979 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Baylor Genetics RCV000007528 SCV001523284 pathogenic Cystic fibrosis 2023-01-27 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000078997 SCV001714830 pathogenic not provided 2021-11-29 criteria provided, single submitter clinical testing
Pars Genome Lab RCV000007528 SCV001736825 pathogenic Cystic fibrosis 2021-05-18 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000007528 SCV001810343 pathogenic Cystic fibrosis 2021-07-22 criteria provided, single submitter clinical testing
Institute of Reproductive Genetics, University of Münster RCV001642199 SCV001860326 pathogenic Obstructive azoospermia 2021-08-23 criteria provided, single submitter clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV000078997 SCV002009129 pathogenic not provided 2021-11-03 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000078997 SCV002019226 pathogenic not provided 2023-07-31 criteria provided, single submitter clinical testing
AiLife Diagnostics, AiLife Diagnostics RCV000078997 SCV002501159 likely pathogenic not provided 2022-03-30 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV000007528 SCV002507318 pathogenic Cystic fibrosis 2019-07-23 criteria provided, single submitter clinical testing
Undiagnosed Diseases Network, NIH RCV000007528 SCV002523164 pathogenic Cystic fibrosis 2018-07-22 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000007528 SCV002573882 pathogenic Cystic fibrosis 2022-09-05 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.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PS3, PM3_STR, PM5_STR, PP3
MGZ Medical Genetics Center RCV000007528 SCV002581402 pathogenic Cystic fibrosis 2022-02-22 criteria provided, single submitter clinical testing
Baylor Genetics RCV003473001 SCV004211622 pathogenic Bronchiectasis with or without elevated sweat chloride 1 2023-10-31 criteria provided, single submitter clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center RCV004018585 SCV005016539 pathogenic Pseudomonas aeruginosa, susceptibility to chronic infection by, in cystic fibrosis 2024-03-14 criteria provided, single submitter clinical testing
OMIM RCV000007528 SCV000027729 pathogenic Cystic fibrosis 2009-11-01 no assertion criteria provided literature only
OMIM RCV000007529 SCV000053488 pathogenic Congenital bilateral aplasia of vas deferens from CFTR mutation 2009-11-01 no assertion criteria provided literature only
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000078997 SCV001550195 pathogenic not provided no assertion criteria provided clinical testing The CFTR p.R117H variant has been reported in the literature as a common variant known to be associated with Cystic Fibrosis (CF) and CF-related diseases, however the phenotype may range from asymptomatic to the classical CF phenotype (Thauvin-Robinet_2013_PMID:23378603; De-Nooijer_2011_PMID:21507732; Thauvin-Robinet_2009_PMID:19880712; Ong_2001_PMID:20301428; White_2001_PMID:11746017; Massie_2001_PMID:11491164; Dasouki_1998_PMID:9557894). The severity of the p.R117H variant has been reported to depend on variation of the poly T tract in intron 9 of the CFTR gene. When the p.R117H variant is found in cis with the 5T variant individuals typically display a more severe phenotype, while individuals with the p.R117H variant and the 7T or 9T variants may have a mild or aymptomatic phenotype (Massie_2001_PMID:11491164; Chmiel_1999_PMID:10103316; Kieswetter_1993_PMID:7506096). The variant was identified in dbSNP (ID: rs78655421) and ClinVar (classified as pathogenic by Ambry Genetics, Laboratory for Molecular Medicine and 17 other submitters; as likely pathogenic by Hudson Alpha Institute for Biotechnology; as uncertain significance by Invitae; and as 'drug response' by PharmGKB). The variant was identified in control databases in 406 of 282346 chromosomes (1 homozygous) at a frequency of 0.001438, and was observed at the highest frequency in the European (non-Finnish) population in 323 of 128902 chromosomes (1 homozygous) (freq: 0.002506) (Genome Aggregation Database March 6, 2019, v2.1.1). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. The p.R117 residue is conserved in mammals and more distantly related organisms, and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) suggest that the variant may impact the protein. Functional evidence indicates that the p.R117H variant causes gating defects in CFTR function and results in reduced channel conductance, but retains some residual activity (Yu_2016_PMID:26846474). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
GeneReviews RCV000007528 SCV001622784 not provided Cystic fibrosis no assertion provided literature only
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV001009478 SCV002507402 pathogenic CFTR-related disorder 2019-07-23 no assertion criteria provided clinical testing

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