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rs78655421

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 13P and 1B. PM1PM5PP3PP5_Very_StrongBP4

The NM_000492.4(CFTR):c.350G>A(p.Arg117His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00214 in 1,613,574 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R117C) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0015 ( 1 hom., cov: 32)
Exomes 𝑓: 0.0022 ( 5 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

11
3
3

Clinical Significance

Pathogenic practice guideline P:37U:1O:2

Conservation

PhyloP100: 9.52
Variant links:
Genes affected
CFTR (HGNC:1884): (CF transmembrane conductance regulator) This gene encodes a member of the ATP-binding cassette (ABC) transporter superfamily. The encoded protein functions as a chloride channel, making it unique among members of this protein family, and controls ion and water secretion and absorption in epithelial tissues. Channel activation is mediated by cycles of regulatory domain phosphorylation, ATP-binding by the nucleotide-binding domains, and ATP hydrolysis. Mutations in this gene cause cystic fibrosis, the most common lethal genetic disorder in populations of Northern European descent. The most frequently occurring mutation in cystic fibrosis, DeltaF508, results in impaired folding and trafficking of the encoded protein. Multiple pseudogenes have been identified in the human genome. [provided by RefSeq, Aug 2017]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1
In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 uncertain in NM_000492.4
PM5
Other missense variant is known to change same aminoacid residue: Variant chr7-117530974-C-T is described in ClinVar as [Pathogenic, drug_response]. Clinvar id is 48688.Status of the report is reviewed_by_expert_panel, 3 stars.
PP3
Multiple lines of computational evidence support a deleterious effect 8: BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, phyloP100way_vertebrate, PROVEAN, REVEL [when AlphaMissense, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
PP5
Variant 7-117530975-G-A is Pathogenic according to our data. Variant chr7-117530975-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 7109.Status of the report is practice_guideline, 4 stars. Variant chr7-117530975-G-A is described in Lovd as [Pathogenic]. Variant chr7-117530975-G-A is described in Lovd as [Likely_pathogenic]. Variant chr7-117530975-G-A is described in Lovd as [Pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.1833263).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CFTRNM_000492.4 linkuse as main transcriptc.350G>A p.Arg117His missense_variant 4/27 ENST00000003084.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CFTRENST00000003084.11 linkuse as main transcriptc.350G>A p.Arg117His missense_variant 4/271 NM_000492.4 P2P13569-1

Frequencies

GnomAD3 genomes
AF:
0.00152
AC:
231
AN:
152170
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000579
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000393
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00188
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00265
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.00149
AC:
373
AN:
250954
Hom.:
1
AF XY:
0.00148
AC XY:
201
AN XY:
135602
show subpopulations
Gnomad AFR exome
AF:
0.000369
Gnomad AMR exome
AF:
0.000610
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00190
Gnomad NFE exome
AF:
0.00265
Gnomad OTH exome
AF:
0.000654
GnomAD4 exome
AF:
0.00220
AC:
3214
AN:
1461404
Hom.:
5
Cov.:
31
AF XY:
0.00213
AC XY:
1545
AN XY:
727012
show subpopulations
Gnomad4 AFR exome
AF:
0.000448
Gnomad4 AMR exome
AF:
0.000694
Gnomad4 ASJ exome
AF:
0.000115
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00140
Gnomad4 NFE exome
AF:
0.00271
Gnomad4 OTH exome
AF:
0.00121
GnomAD4 genome
AF:
0.00152
AC:
231
AN:
152170
Hom.:
1
Cov.:
32
AF XY:
0.00144
AC XY:
107
AN XY:
74340
show subpopulations
Gnomad4 AFR
AF:
0.000579
Gnomad4 AMR
AF:
0.000393
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00188
Gnomad4 NFE
AF:
0.00265
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.00236
Hom.:
1
Bravo
AF:
0.00140
TwinsUK
AF:
0.00243
AC:
9
ALSPAC
AF:
0.00259
AC:
10
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00209
AC:
18
ExAC
AF:
0.00152
AC:
185
EpiCase
AF:
0.00169
EpiControl
AF:
0.00190

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:37Uncertain:1Other:2
Revision: practice guideline
LINK: link

Submissions by phenotype

Cystic fibrosis Pathogenic:16Uncertain:1Other:1
Pathogenic, criteria provided, single submitterclinical testingCourtagen Diagnostics Laboratory, Courtagen Life SciencesApr 23, 2014- -
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsOct 07, 2021The 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. -
not provided, no classification providedliterature onlyGeneReviews-- -
Pathogenic, criteria provided, single submittercurationInstitute of Human Genetics, University of Leipzig Medical CenterSep 05, 2022This 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 -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsJan 27, 2023- -
Pathogenic, criteria provided, single submitterclinical testingMGZ Medical Genetics CenterFeb 22, 2022- -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpApr 11, 2016Variant 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. -
Likely pathogenic, criteria provided, single submitterresearchHudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for BiotechnologyNov 04, 2014- -
Pathogenic, criteria provided, single submitterclinical testingGenome-Nilou LabJul 22, 2021- -
Pathogenic, criteria provided, single submitterclinical testingMendelicsNov 05, 2018- -
Pathogenic, no assertion criteria providedliterature onlyOMIMNov 01, 2009- -
Pathogenic, criteria provided, single submitterclinical testingPars Genome LabMay 18, 2021- -
Pathogenic, criteria provided, single submitterclinical testingUndiagnosed Diseases Network, NIHJul 22, 2018- -
Uncertain significance, criteria provided, single submitterclinical testingInvitaeJan 31, 2024This 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. -
Pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017The 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. -
Pathogenic, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenJul 23, 2019- -
Pathogenic, practice guidelinecurationAmerican College of Medical Genetics and Genomics (ACMG)Mar 03, 2004- -
Pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Oct 18, 2019NM_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. -
not provided Pathogenic:13
Pathogenic, criteria provided, single submitterclinical testingGenomic Research Center, Shahid Beheshti University of Medical SciencesMay 03, 2020- -
Pathogenic, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicNov 29, 2021- -
Pathogenic, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoJan 09, 2020The 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)). -
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)May 15, 2017- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxMay 07, 2018The 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. -
Pathogenic, criteria provided, single submitterclinical testingInstitute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU DresdenNov 03, 2021- -
Likely pathogenic, criteria provided, single submitterclinical testingAiLife Diagnostics, AiLife DiagnosticsMar 30, 2022- -
Pathogenic, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsFeb 11, 2015- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Medical Genetics and Applied Genomics, University Hospital TübingenOct 23, 2020- -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityJul 31, 2023- -
Pathogenic, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-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. -
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 13, 2023The 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. -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenAug 01, 2022CFTR: PS3:Very Strong, PP4:Strong -
Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingBaylor Genetics-- -
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineOct 24, 2018The 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. -
CFTR-related disorders Pathogenic:2
Pathogenic, criteria provided, single submittercurationCFTR-FranceJan 29, 2018- -
Pathogenic, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenJul 23, 2019- -
Obstructive azoospermia Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInstitute of Reproductive Genetics, University of MünsterAug 23, 2021- -
Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsApr 13, 2022- -
Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsOct 31, 2023- -
Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMNov 01, 2009- -
ivacaftor response - Efficacy Other:1
drug response, reviewed by expert panelcurationPharmGKBMar 24, 2021PharmGKB 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. Drug-variant association: Efficacy

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.30
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Pathogenic
0.41
Cadd
Pathogenic
27
Dann
Pathogenic
1.0
Eigen
Pathogenic
0.72
Eigen_PC
Pathogenic
0.69
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.93
D;D;D;D;D;D
M_CAP
Pathogenic
0.89
D
MetaRNN
Benign
0.18
T;T;T;T;T;T
MetaSVM
Pathogenic
1.1
D
MutationTaster
Benign
1.0
A;A
PrimateAI
Uncertain
0.54
T
PROVEAN
Pathogenic
-5.0
D;N;.;.;N;.
REVEL
Pathogenic
0.81
Sift
Pathogenic
0.0
D;D;.;.;D;.
Sift4G
Pathogenic
0.0
D;D;.;.;D;.
Polyphen
1.0
.;D;.;.;.;.
Vest4
0.88
MVP
1.0
MPC
0.011
ClinPred
0.058
T
GERP RS
5.7
Varity_R
0.55
gMVP
0.92

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs78655421; hg19: chr7-117171029; COSMIC: COSV50042918; API