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

dbSNP: rs78655421

Total submissions: 42

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.
Labcorp Genetics (formerly Invitae), Labcorp	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	2023-01-31	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	2024-09-09	criteria provided, single submitter	clinical testing	Criteria applied: PS3,PM3_STR,PM5_STR,PP3; Identified as compund heterozygous with NM_000492.4:c.1521_1523del
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	2024-03-30	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
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000078997	SCV005197448	likely pathogenic	not provided	2022-05-27	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