ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.350G>A (p.Arg117His) (rs78655421)

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Total submissions: 23
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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 2018-03-27 reviewed by expert panel curation PharmGKB Level of Evidence 1A: Annotation for a variant-drug combination in a CPIC or medical society-endorsed PGx guideline, or implemented at a PGRN site or in another major health system.
Invitae RCV000007528 SCV000074930 uncertain significance Cystic fibrosis 2020-01-03 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 117 of the CFTR protein (p.Arg117His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs78655421, ExAC 0.3%). 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 has not been associated with cystic fibrosis (PMID: 21507732, 7506096, 23974870). ClinVar contains an entry for this variant (Variation ID: 7109, 209047). 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). 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 contribute to cystic fibrosis but may contribute to CAVD. 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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics 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 2017-05-22 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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 2015-11-18 criteria provided, single submitter clinical testing
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 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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, Partners HealthCare 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 disorders 2018-01-29 criteria provided, single submitter curation
Ambry Genetics RCV001020485 SCV001181971 pathogenic Inborn genetic diseases 2018-10-05 criteria provided, single submitter clinical testing Deficient protein function by in vitro/ex vivo assay;Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous
Myriad Women's Health, 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 Praxis fuer Humangenetik Tuebingen RCV000078997 SCV001250499 pathogenic not provided 2020-02-01 criteria provided, single submitter clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000078997 SCV001251861 pathogenic not provided 2020-05-03 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

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