7-117611649-C-T

Variant names:

• chr7-117611649-C-T
• rs202179988
• NM_000492.4:c.3208C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM5 PP2 PP3_Moderate

The NM_000492.4(CFTR):​c.3208C>T​(p.Arg1070Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00008 in 1,613,480 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as drug response (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1070Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000085 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: drug response reviewed by expert panel P:19 O:1
• Conservation: PhyloP100: 3.94
• Publications: 103 publications found

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]

CFTR Gene-Disease associations (from GenCC):

• cystic fibrosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet
• congenital bilateral absence of vas deferens

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary chronic pancreatitis

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000083622 (HGNC:40145):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_000492.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-117611650-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 53686.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 197 curated pathogenic missense variants (we use a threshold of 10). The gene has 46 curated benign missense variants. Gene score misZ: -3.1397 (below the threshold of 3.09). Trascript score misZ: -1.0868 (below the threshold of 3.09). GenCC associations: The gene is linked to hereditary chronic pancreatitis, cystic fibrosis, congenital bilateral absence of vas deferens.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.86

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.3208C>T	p.Arg1070Trp	missense_variant	Exon 20 of 27	ENST00000003084.11	NP_000483.3
CFTR-AS2	NR_199597.1	n.177+4580G>A		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.3208C>T	p.Arg1070Trp	missense_variant	Exon 20 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152052 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000478 AC: 12 AN: 250962 AF XY: 0.0000295

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000871

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000617

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000849 AC: 124 AN: 1461310 Hom.: 0 Cov.: 31 AF XY: 0.0000729 AC XY: 53 AN XY: 726964

African (AFR) AF: 0.0000299 AC: 1 AN: 33458

American (AMR) AF: 0.0000896 AC: 4 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39682

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000103 AC: 114 AN: 1111678

Other (OTH) AF: 0.0000331 AC: 2 AN: 60354

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152170 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74388

African (AFR) AF: 0.0000482 AC: 2 AN: 41528

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.0000780 Hom.: 0

Bravo AF: 0.0000604

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000412 AC: 5

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: drug response

Submissions summary: Pathogenic:19 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:7

Jan 21, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R1070W pathogenic mutation (also known as c.3208C>T), located in coding exon 20 of the CFTR gene, results from a C to T substitution at nucleotide position 3208. The arginine at codon 1070 is replaced by tryptophan, an amino acid with dissimilar properties. In one study, this mutation was identified in conjunction with a second CFTR alteration in 24 individuals with pancreatic sufficient cystic fibrosis or congenital bilateral absence of the vas deferens (CBAVD) (Krasnov KV et al. Hum. Mutat., 2008 Nov;29:1364-72). In vitro functional studies showed that cells with this mutation have significantly decreased chloride conductance compared to wild type (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7; Van Goor F et al. J. Cyst. Fibros., 2014 Jan;13:29-36) and CFTR protein with this mutation was able to process into mature protein but with decreased efficiency compared to wild-type (Krasnov KV et al. Hum. Mutat., 2008 Nov;29:1364-72). The p.R1070W alteration has been reported as a variant of varying clinical consequences (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). 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 the supporting evidence, this variant is interpreted as a disease-causing mutation. -

Nov 05, 2018

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 26, 2018

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Nov 02, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.3208C>T (p.Arg1070Trp) missense variant is well described in the literature as a mild or intermediate variant and is reported to have varying clinical consequences including pancreatic sufficient cystic fibrosis (CF) and congenital bilateral absence of the vas deferens (CBAVD). The p.Arg1070Trp variant has been identified in a compound heterozygous state in at least four studies in six individuals with CBAVD (Jezequel et al. 1995; Mickle et al. 2000; Jezequel et al. 2000; Steiner et al. 2011). The variant has also been reported as part of a complex allele in a compound heterozygous state with a pathogenic splice site variant in a proband with CF (de Prada Merino et al. 2010). Functional studies by Van Goor et al. (2014) demonstrated the p.Arg1070Trp variant resulted in 8% of wild type levels of chloride ion transport. The p.Arg1070Trp variant is reported in the CFTR2 mutation database in a total of 13 alleles (Sosnay et al. 2013), and is described as a "mutation of varying clinical consequence." Incomplete penetrance is documented in association with the p.Arg1070Trp variant; not all individuals who carry this variant along with a second disease-causing CFTR variant in trans will display symptoms of a CFTR-related disorder (CFTR2 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.000125 in the African population of the Genome Aggregation Database. Based on the collective evidence, the p.Arg1070Trp 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. -

Oct 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1070 of the CFTR protein (p.Arg1070Trp). This variant is present in population databases (rs202179988, gnomAD 0.01%). This missense change has been observed in individual(s) with cystic fibrosis and congenital absence of the vas deferens (PMID: 7539342, 10923036, 12167682, 15070876). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 53685). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CFTR function (PMID: 18951463, 23891399). For these reasons, this variant has been classified as Pathogenic. -

Dec 22, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 20, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CFTR c.3208C>T (p.Arg1070Trp) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 250962 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing CFTR-Related Diseases (4.8e-05 vs 0.013), allowing no conclusion about variant significance. c.3208C>T has been reported in the literature in compound heterozygosity with another pathogenic variant in multiple individuals affected with CFTR-Related Diseases, primarily CBAVD (e.g. Jezequel_1995, Steiner_2011) and Non-Classic Cystic Fibrosis (e.g. McGinnis_2005, Sosnay_2013). These data indicate that the variant is likely to be associated with disease. A worldwide survey of patients with the p.Arg1070Trp variant identified 24 patients with complete clinical data (21 of which had the common pathogenic variant p.Phe508del or another severe CFTR mutation), and included 15 patients with CBAVD, 9 with non-classic CF, and 1 with classic CF phenotypes (Krasnov_2008). A second large survey that collected data from CF registries and clinics in the US and Europe reported the variant in a total of 13 CF alleles, but indicated that only 20% of the individuals were pancreatic-insufficient, with a mean lung function of 93.7%. 16.7% of these patients had tested positive for Pseudomonas (Sosnay_2013). Collectively, the clinical data on patients with this variant suggests that c.3208C>T is most likely a relatively mild mutation that is most often associated with either pancreatic-sufficient non-classic CF or CBAVD when present in trans with a more severe CFTR mutation. Several functional studies evaluating an impact on protein function have reported conflicting conclusions regarding the effects of this variant. One study reported that chloride channel function in cells expressing the variant was comparable to wild-type (e.g. Mickle_2000), however, it has also been reported that chloride conductance in cells expressing the variant was <10% that of wild-type (e.g. Van Goor_2013, Sosnay_2013). CFTR maturation and the amount of protein expression was 91% and 67.8% of the wild-type as measured in HeLa cells and FRT cells, respectively (Sosnay_2013), and the variant was reported to retain localization to the apical membrane, albeit less efficiently than the wild-type protein (e.g. Krasnov_2008). Eleven submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified teh variant VUS (n=1), likely pathogenic (n=1) and pathogenic (n=9). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:3

Dec 14, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In the published literature, the variant has been reported in several individuals affected with CBAVD or non-classic CF (PMID: 18951463 (2008), 20880762 (2010), 21520337 (2011), 26708955 (2016)). In addition, in vitro functional studies show this variant has a deleterious effect on CFTR protein processing, localization, and function (PMID: 18951463 (2008), 23974870 (2013), 23891399 (2014)). However, it was observed to have high chloride channel function in an earlier study (PMID: 10762539 (2000)). Based on the available information, this variant is classified as pathogenic. -

Aug 15, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.3208C>T; p.Arg1070Trp variant (rs202179988) is reported in the literature in dozens of individuals affected with cystic fibrosis (CF) or other CFTR-related disorders (Jezequel 1995, Krasnov 2008, Sosnay 2013, CFTR2 database). Most patients carrying p.Arg1070Trp and a second CF-causing variant exhibit non-classic CF or milder symptoms such as congenital absence of the vas deferens or pancreatitis, although a minority of patients are reported with pancreatic-insufficient CF (Krasnov 2008, CFTR2 database). Functional studies suggest p.Arg1070 affects CFTR function and reduces chloride transport activity (Van Goor 2014). This variant is reported as likely pathogenic or pathogenic in ClinVar (Variation ID: 53685), and it is found in the general population with an overall frequency of 0.005% (14/282342 alleles) in the Genome Aggregation Database. Additionally, other amino acid substitutions at this codon (p.Arg1070Gln, p.Arg1070Pro) have been reported in individuals with CF or CFTR-related disorders and are considered disease-causing (Krasnov 2008, Sosnay 2013, CFTR2 database). Based on available information, the p.Arg1070Trp variant is considered to be pathogenic with varying clinical consequences. References: CFTR2 database: http://cftr2.org/ Jezequel P et al. Structural analysis of CFTR gene in congenital bilateral absence of vas deferens. Clin Chem. 1995 Jun;41(6 Pt 1):833-5. Krasnov KV et al. Localization studies of rare missense mutations in cystic fibrosis transmembrane conductance regulator (CFTR) facilitate interpretation of genotype-phenotype relationships. Hum Mutat. 2008 Nov;29(11):1364-72. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 Oct;45(10):1160-7. 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. -

Dec 05, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: reduced cell surface expression and chloride transport with defective channel gating (Seibert et al., 1996; Sosnay et al., 2013; VanGoor et al., 2014); Observed with a pathogenic variant in patients with cystic fibrosis or CFTR-related disorders (Jezequel et al., 2000; McGinniss et al., 2005; Krasnov et al., 2008; Lebecque et al., 2011; Baldwin et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 8530001, 31036917, 27171515, 30873022, 25087612, 21520337, 23891399, 20460946, 21228398, 27469177, 8662892, 18951463, 10762539, 23974870, 7539342, 26708955, 20837875, 17331079, 11101688, 26014425, 16189704, 12955726, 12815607, 20880762, 35327663, 31268981, 34996830, 33374015, 35451201) -

Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:2

-

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 11, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg1070Trp variant in CFTR has been reported in >20 compound heterozygous individuals (the majority carrying p.Phe508del) primarily affected by milder for ms of CFTR-related disorders (congenital bilateral absence of the vas deferens a nd cystic fibrosis) and more than half of these individuals were reported to hav e normal to low sweat chloride levels (Jezequel 1995, Feldmann 2003, Krasnov 200 8, Pelletier 2010, de Prada Merino 2010, Steiner 2011, Sosnay 2013). In addition , this variant has been identified in 4/66100 of European chromosomes and 1/1034 0 African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.bro adinstitute.org; dbSNP rs202179988). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessiv e carrier frequency. In vitro functional studies provide some evidence that the p.Arg1070Trp variant may impact protein function (Krasnov 2008, Sosnay 2013, Van Goor 2014). However, these types of assays may not accurately represent biologi cal function. In summary, this variant meets our criteria to be classified as pa thogenic for CTFR-related disorders including CBAVD and cystic fibrosis in an au tosomal recessive manner (http://www.partners.org/personalizedmedicine/LMM) base d upon multiple co-occurrences with pathogenic variants and its low frequency in the general population. -

CFTR-related disorder Pathogenic:2

Jun 06, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CFTR c.3208C>T variant is predicted to result in the amino acid substitution p.Arg1070Trp. This variant has been reported in cohorts of individuals with suspected cystic fibrosis (see, for example, Krasnov et al. 2008. PubMed ID: 18951463; Pelletier et al. 2010. PubMed ID: 20460946; Ferec et al. 1995. PubMed ID: 8530001) as well as in the compound heterozygous state in patients with congenital bilateral absence of vas deferens (Jezequel et al. 1995. PubMed ID: 7539342; Steiner et al. 2011. PubMed ID: 21520337). In vitro studies suggest that this variant results in a defect of normal CFTR processing (Van Goor et al. 2013. PubMed ID: 23891399; Sosnay et al. 2013. PubMed ID: 23974870), with at least one study suggesting that the p.Arg1070Trp variant may be a more mildly deleterious allele (Krasnov et al. 2008. PubMed ID: 18951463). This variant is reported in 0.0085% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as likely pathogenic. -

Dec 22, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Pathogenic:1

Feb 08, 2020

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital bilateral absence of vas deferens Pathogenic:1

Mar 30, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change is predicted to replace arginine with tryptophan at codon 1070 of the CFTR protein, p.(Arg1070Trp). The arginine residue is evolutionarily conserved (100 vertebrates, UCSC), and is located in the fourth cytoplasmic loop of the cystic fibrosis transmembrane (CL4). There is a large physicochemical difference between arginine and tryptophan. The variant is present in a large population cohort at a frequency of 0.005%, which is consistent with recessive disease (rs202179988, 14/282,342 alleles, 0 homozygotes in gnomAD v2.1). It is classified as a CFTR variant of varying clinical consequences, and has been identified with a second pathogenic allele (mainly p.Phe508del) in non-classic pancreatic cystic fibrosis (CF), congenital bilateral absence of the vas deferens, and recurrent pancreatitis (for example PMID: 18951463, 31268981). The variant has also been identified as part of a complex allele that causes classic CF, when found in trans with a second pathogenic variant (PMID: 20880762). In vitro functional assays demonstrate that the variant causes mild defects on chloride transport and is inserted into the apical membrane at reduced levels (PMID: 8662892, 18951463, 23891399). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). Additionally, there is a different missense change (p.Arg1070Gln) at the same position determined to be pathogenic (ClinVar). Based on the classification scheme RMH Modified ACMG Guidelines v1.3.2, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PM5, PS3_Supporting, PM2_Supporting, PP3. -

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

Apr 11, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Mar 28, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cystic fibrosis;C5924204:CFTR-related disorder Pathogenic:1

Jan 29, 2018

CFTR-France

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD -

ivacaftor response - Efficacy Other:1

Mar 24, 2021

PharmGKB

Significance: drug response

Review Status: reviewed by expert panel

Collection Method: 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. Drug-variant association: Efficacy

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	D;.;.;D;.
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Benign	1.6	L;.;.;.;.
PhyloP100		3.9
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.4	D;.;.;D;.
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0040	D;.;.;D;.
Sift4G	Pathogenic	0.0	D;.;.;D;.
Polyphen		1.0	D;.;.;.;.
Vest4		0.98
MVP		0.99
MPC		0.017
ClinPred		0.55	D
GERP RS		5.7
PromoterAI		0.012	Neutral
Varity_R		0.65
gMVP		0.98
Mutation Taster		=5/95	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs202179988; hg19: chr7-117251703;