rs75541969
Positions:
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
NM_000492.4 missense
Scores
7
9
3
Clinical Significance
Conservation
PhyloP100: 5.26
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 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=2, drug_response=1, Pathogenic=24}. 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/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CFTR | NM_000492.4 | c.3454G>C | p.Asp1152His | missense_variant | 21/27 | ENST00000003084.11 | NP_000483.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CFTR | ENST00000003084.11 | c.3454G>C | p.Asp1152His | missense_variant | 21/27 | 1 | NM_000492.4 | ENSP00000003084 | P2 | |
| ENST00000456270.1 | n.177+1530C>G | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes 0.000316 AC: 48AN: 152040Hom.: 1 Cov.: 31
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GnomAD3 exomes AF: 0.000398 AC: 100AN: 250946Hom.: 0 AF XY: 0.000361 AC XY: 49AN XY: 135624
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GnomAD4 exome AF: 0.000407 AC: 593AN: 1457986Hom.: 0 Cov.: 29 AF XY: 0.000374 AC XY: 271AN XY: 725492
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GnomAD4 genome 0.000316 AC: 48AN: 152040Hom.: 1 Cov.: 31 AF XY: 0.000337 AC XY: 25AN XY: 74280
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ClinVar
Significance: drug response
Submissions summary: Pathogenic:36Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not provided Pathogenic:14
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 05, 2021 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Aug 04, 2021 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Oct 02, 2017 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 12, 2018 | 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. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 03, 2023 | The CFTR c.3454G>C (p.Asp1152His) variant has been reported in the published literature in individuals with cystic fibrosis and may be associated with a milder presentation than typical pathogenic variants in CFTR (PMIDs: 27659740 (2017), 27214204 (2016), 27086061 (2016), 26755536 (2016), 25910067 (2015), 25583415 (2015)). This variant is also reported in individuals with CFTR-related disorders (PMIDs: 7739684 (1995), 22020151 (2012), 23951356 (2013), 27171515 (2016), 27738188 (2017)). In addition, published functional studies demonstrate that this variant partially reduces chloride transport activity, affects proper chloride channel gating, alters bicarbonate conductance, and results in decreased conductance and 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 uninformative in the assessment of its pathogenicity. Based on the available information, this variant is classified as likely pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 24, 2023 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Oct 28, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 22, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | CFTR: PM3:Very Strong, PM2:Supporting, PS3:Supporting - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Mar 08, 2023 | - - |
Cystic fibrosis Pathogenic:13
| Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 22, 2021 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 16, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 26, 2021 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Jul 09, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 13, 2022 | 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. - |
| Pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Jul 05, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 24, 2024 | 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). 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%. 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Aug 23, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Nov 05, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 22, 2018 | 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. - |
| Pathogenic, no assertion criteria provided | research | Division of Human Genetics, Children's Hospital of Philadelphia | Nov 13, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 11, 2019 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 01, 2023 | - - |
CFTR-related disorder Pathogenic:3
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 21, 2018 | - - |
| Likely pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 22, 2024 | 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. - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Aug 23, 2021 | - - |
Obstructive azoospermia Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Reproductive Genetics, University of Münster | Mar 16, 2022 | - - |
Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Cystic fibrosis;na:CFTR-related disorder Pathogenic:1
| Pathogenic, criteria provided, single submitter | curation | CFTR-France | Jan 29, 2018 | when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD - |
Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 30, 2024 | - - |
Male infertility Pathogenic:1
| Pathogenic, no assertion criteria provided | provider interpretation | MAGI's Lab - Research, MAGI Group | - | - - |
Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 13, 2018 | 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] - |
ivacaftor response - Efficacy Other:1
| drug response, reviewed by expert panel | curation | PharmGKB | Mar 24, 2021 | 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;.;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;.;.;.;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.;.;D;.
REVEL
Pathogenic
Sift
Uncertain
D;.;.;D;.
Sift4G
Uncertain
D;.;.;D;.
Polyphen
P;.;.;.;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at