rs75541969

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM2PP5_StrongBP4

The NM_000492.4(CFTR):c.3454G>C(p.Asp1152His) variant causes a missense change. The variant allele was found at a frequency of 0.000398 in 1,610,026 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

Frequency

Genomes: 𝑓 0.00032 ( 1 hom., cov: 31)

Exomes 𝑓: 0.00041 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

drug response reviewed by expert panel P:37O:1

Conservation

PhyloP100: 5.26

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]

CFTR links:

ENSG00000083622 (HGNC:):

ENSG00000083622 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 7-117614699-G-C is Pathogenic according to our data. Variant chr7-117614699-G-C is described in ClinVar as [drug_response]. Clinvar id is 35867.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, drug_response=1, Pathogenic=26}. Variant chr7-117614699-G-C is described in Lovd as [Pathogenic]. Variant chr7-117614699-G-C is described in Lovd as [Pathogenic]. Variant chr7-117614699-G-C is described in Lovd as [Likely_pathogenic]. Variant chr7-117614699-G-C is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.188137). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4 link	c.3454G>C	p.Asp1152His	missense_variant	Exon 21 of 27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 link	c.3454G>C	p.Asp1152His	missense_variant	Exon 21 of 27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.000316

AC:

AN:

152040

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000515

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000398

AC:

100

AN:

250946

Hom.:

AF XY:

0.000361

AC XY:

AN XY:

135624

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000869

Gnomad ASJ exome

AF:

0.00258

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000335

Gnomad OTH exome

AF:

0.000655

GnomAD4 exome

AF:

0.000407

AC:

593

AN:

1457986

Hom.:

Cov.:

AF XY:

0.000374

AC XY:

271

AN XY:

725492

show subpopulations

Gnomad4 AFR exome

AF:

0.000150

Gnomad4 AMR exome

AF:

0.000828

Gnomad4 ASJ exome

AF:

0.00246

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000411

Gnomad4 OTH exome

AF:

0.000465

GnomAD4 genome

AF:

0.000316

AC:

AN:

152040

Hom.:

Cov.:

AF XY:

0.000337

AC XY:

AN XY:

74280

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000515

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.000512

Hom.:

Bravo

AF:

0.000378

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000264

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.000474

ClinVar

Significance: drug response

Submissions summary: Pathogenic:37Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:13

Oct 01, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 09, 2019

Johns Hopkins Genomics, Johns Hopkins University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 22, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.3454G>C (p.Asp1152His) missense variant has been described in 12 studies in patients with CFTR-related disorders, including in at least 22 in a homozygous state and 179 in a compound heterozygous state (Chillon et al. 1995; Dayangac et al. 2004; Highsmith et al. 2005; Mussaffi et al. 2006; Augarten et al. 2008; Burgel et al. 2010; Peleg et al. 2011; Steiner et al. 2011; Tomaiuolo et al. 2011; Sosnay et al. 2013; LaRusch et al. 2014; Terlizzi et al. 2015). The p.Asp1152His variant, when in combination with another variant known to cause CFTR-related disorders, is associated with an extremely variable phenotype ranging from asymptomatic to cystic fibrosis. The variant is often associated with mild clinical expression, mild pulmonary disease and pancreatic sufficiency (Augarten et al. 2008; Burgel et al. 2010; La Rush et al. 2014). The p.Asp1152His variant was found in a heterozygous state in one of 2957 controls and is reported at a frequency of 0.002859 in the Ashkenazi Jewish population of the Genome Aggregation Database. Functional studies on the p.Asp1152His variant showed chloride transport activity is 57.4% of the wild type (Van Goor et al. 2014). La Rusch et al. (2014) report that the p.Asp1152His variant causes a narrowing of the channel diameter which would affect conductance properties. The p.Asp1152His variant was shown to exhibit normal chloride function in HEK293 cells with significantly reduced bicarbonate permeability and conductance (LaRusch et al. 2014). Vankeerberghen et al. (1998) demonstrated in Xenopus oocytes that the p.Asp1152His variant did not alter the permeability sequence of the CFTR channels but led to whole cell cAMP activated chloride currents that were significantly reduced compared to wild type indicating that the variant interfere with the proper gating of the chloride channels. Based on the collective evidence, the p.Asp1152His 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. -

Jul 22, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D1152H pathogenic mutation (also known as c.3454G>C), located in coding exon 21 of the CFTR gene, results from a G to C substitution at nucleotide position 3454. The aspartic acid at codon 1152 is replaced by histidine, an amino acid with similar properties. In one study, 45 individuals with a p.D1152H allele in trans with another CFTR mutation were identified with features including bronchiectasis and congenital bilateral absence of the vas deferens (CBAVD) (Burgel PR et al. Clin. Genet., 2010 Apr;77:355-64). Numerous studies have concluded this mutation is often associated with a mild cystic fibrosis presentation or CFTR-related disorder characterized by mild pulmonary disease, varying clinical expression, and prolonged survival (Schulz A et al. J. Cyst. Fibros., 2016 Sep;15:641-4; Gaitch N et al. Pancreatology Apr;16:515-22; Lucarelli M et al. Mol. Med., 2015 Apr;21:257-75) and it has been described as a variant of varying clinical consequences (VVCC) (Sosnay PR et al. Pediatr. Clin. North Am., 2016 08;63:585-98; Salinas DB et al. PLoS ONE, 2016 May;11:e0155624). Functional in vitro studies found that cells carrying this pathogenic mutation retained the ability to conduct chloride (Sosnay PR et al. Nat. Genet. 2013 Oct; 45(10):1160-7). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Nov 11, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000492.3(CFTR):c.3454G>C(D1152H) is classified as pathogenic in the context of cystic fibrosis and is associated with a broad spectrum of disease, ranging from clinically asyptomatic to classic cystic fibrosis. Sources cited for classification include the following: PMID 9804160, 19843100, 18301294, 22156145 and 23974870. Classification of NM_000492.3(CFTR):c.3454G>C(D1152H) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Aug 23, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 05, 2017

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Oct 26, 2021

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Nov 13, 2015

Division of Human Genetics, Children's Hospital of Philadelphia

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Nov 05, 2018

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 16, 2015

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 1152 of the CFTR protein (p.Asp1152His). This variant is present in population databases (rs75541969, gnomAD 0.3%). This missense change has been observed in individuals with congenital absence of the vas deferens and classic cystic fibrosis (PMID: 7739684, 11883825, 15858154, 15987793, 16429425, 17003641, 17594398, 18301294, 19843100, 20460946, 21520337, 22156145, 23082198, 23951356, 25304080). ClinVar contains an entry for this variant (Variation ID: 35867). 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: 9804160, 23891399, 25033378). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:13

Sep 07, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.3454G>C (p.Asp1152His) variant has been reported in the published literature in many individuals affected with either cystic fibrosis (may be milder than the classical presentation) (PMIDs: 27659740 (2017), 27214204 (2016), 27086061 (2016), 26755536 (2016), 25910067 (2015), 25583415 (2015)) or a CFTR-related disease (PMIDs: 7739684 (1995), 22020151 (2012), 23951356 (2013), 27171515 (2016), 27738188 (2017)). It is described as a variant having varying clinical consequences (CFTR2, https://cftr2.org/). In addition, published functional studies demonstrated that this variant partially reduces chloride transport activity, affects proper channel gating, and reduces bicarbonate permeability (PMIDs: 32414100 (2020), 25033378 (2014), 23891399 (2014), 9804160 (1998)). The frequency of this variant in the general population, 0.0026 (27/10360 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -

May 22, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 04, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 12, 2018

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The D1152H pathogenic variant has been reported previously is association with cystic fibrosis and congenital bilateral absence of the vas deferens (Chillon et al., 1995; Burgel et al., 2010; Terlizzi et al., 2015). A retrospective case review revealed that the patients homozygous and compound heterozygous for the D1152H variant exhibited very mild clinical expression (Terlizzi et al., 2015). The D1152H variant is observed in 29/10,142 (0.3%) alleles from individuals of Ashkenazi Jewish background in large population cohorts, and no individuals were reported to be homozygous (Lek et al., 2016). The D1152H variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In vitro functional studies indicated that the D1152H variant results in a protein whose chloride transport is approximately 57% that of wild-type (VanGoor et al., 2014; LaRusch et al., 2014). We interpret D1152H as a pathogenic variant. -

Oct 02, 2017

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 28, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 05, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CFTR: PM3:Very Strong, PM2:Supporting, PS3:Supporting -

Mar 08, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CFTR-related disorder

Pathogenic:3

Aug 22, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CFTR c.3454G>C variant is predicted to result in the amino acid substitution p.Asp1152His. This variant has been found in 358 patients who also carried a p.Phe508del variant (cftr2.org). These individuals had slightly elevated chloride concentration of 43 mEq/L on a sweat test (normal <40 mEq/L). Individuals less than 20 years of age had normal lung function, but 27% had pancreatic insufficiency (cftr2.org; Sosnay et al. 2013. PubMed ID: 23974870). This variant, when present with a second pathogenic variant, has been reported in patients with variable clinical presentations including bronchiectasis, pancreas insufficiency, chronic cough, and congenital bilateral absence of the vas deferens (Feldmann et al. 2003. PubMed ID: 12955726; Terlizzi et al. 2015. PubMed ID: 25583415). This variant is reported in 0.26% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as likely pathogenic. -

Aug 23, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 21, 2018

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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:2

Apr 12, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 28, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.3454G>C; p.Asp1152His variant (rs75541969) is reported in the literature in multiple individuals affected with classic cystic fibrosis or CFTR-related disorders (Chillon 1995, Gallati 2009, Highsmith 2005, LaRusch 2014, Masson 2013, Steiner 2011, Sosnay 2013, CFTR2 database). This variant is also reported in ClinVar (Variation ID: 35867), and is found in the general population with an overall allele frequency of 0.038% (106/282326 alleles) in the Genome Aggregation Database. The aspartic acid at codon 1152 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.657). Functional characterization of the variant protein indicates a significant reduction in chloride and bicarbonate transport activity (LaRusch 2014, Sosnay 2013, Van Goor 2014, Vankeerberghen 1998). Genotype-phenotype correlation studies have demonstrated that this variant, in combination with another pathogenic CFTR variant (e.g. p.Phe508del), is associated with highly variable clinical presentations, ranging from asymptomatic to pancreatic insufficient CF (Burgel 2010, Mussaffi 2006, Terlizzi 2015, CFTR2 database). Based on available information, the p.Asp1152His variant is classified as pathogenic with varying clinical consequences. References: Link to CFTR2 database: http://cftr2.org/ Burgel P et al. Non-classic cystic fibrosis associated with D1152H CFTR mutation. Clin Genet. 2010; 77(4):355-64. PMID: 19843100. Chillon M et al. Mutations in the cystic fibrosis gene in patients with congenital absence of the vas deferens. N Engl J Med. 1995; 332(22):1475-80. PMID: 7739684. Gallati S et al. Cystic fibrosis transmembrane conductance regulator mutations in azoospermic and oligospermic men and their partners. Reprod Biomed Online. 2009; 19(5):685-94. PMID: 20021716. Highsmith WE Jr et al. A CFTR mutation (D1152H) in a family with mild lung disease and normal sweat chlorides. Clin Genet. 2005; 68(1):88-90. PMID: 15952991. 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; 10(7):e1004376. PMID: 25033378. Masson E et al. A conservative assessment of the major genetic causes of idiopathic chronic pancreatitis: data from a comprehensive analysis of PRSS1, SPINK1, CTRC and CFTR genes in 253 young French patients. PLoS One. 2013; 8(8):e73522. PMID: 23951356. Mussaffi H et al. Cystic fibrosis mutations with widely variable phenotype: the D1152H example. Pediatr Pulmonol. 2006; 41(3):250-4. PMID: 16429425. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013; 45(10):1160-7. PMID: 23974870. Steiner B et al. Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. Hum Mutat. 2011; 32(8):912-20. PMID: 21520337. Terlizzi V et al. Clinical expression of patients with the D1152H CFTR mutation. J Cyst Fibros. 2015; 14(4):447-52. PMID: 25583415. 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; 13(1):29-36. PMID: 23891399. Vankeerberghen A et al. Characterization of 19 disease-associated missense mutations in the regulatory domain of the cystic fibrosis transmembrane conductance regulator. Hum Mol Genet. 1998; 7(11):1761-9. PMID: 9736778. -

Obstructive azoospermia

Pathogenic:1

Mar 16, 2022

Institute of Reproductive Genetics, University of Münster

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Pathogenic:1

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Mar 30, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Male infertility

Pathogenic:1

MAGI's Lab - Research, MAGI Group

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

- -

Congenital bilateral aplasia of vas deferens from CFTR mutation

Pathogenic:1

Feb 13, 2018

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. [PMID 7739684, 26990548, 22020151, 18301294, 19843100, 18456578, 19212293, 22310382, 20021716, 24082139, 25033378, 25033378, 22975760, 11547256, 23951356, 12124706, 27171515, 22156145, 20460946, 17617039, 23974870, 21520337, 25087612, 25583415, 21679131, 23891399] -

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

0.86

BayesDel_addAF

Uncertain

0.045

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.80

D;.;.;T;.

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;D;D;D;D

M_CAP

Pathogenic

0.79

MetaRNN

Benign

0.19

T;T;T;T;T

MetaSVM

Benign

-0.38

MutationAssessor

Uncertain

2.8

M;.;.;.;.

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-2.7

D;.;.;D;.

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0050

D;.;.;D;.

Sift4G

Uncertain

0.013

D;.;.;D;.

Polyphen

0.57

P;.;.;.;.

Vest4

0.92

MVP

0.99

MPC

0.011

ClinPred

0.12

GERP RS

5.9

Varity_R

0.71

gMVP

0.90

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over