ClinVar Genomic variation as it relates to human health
NM_000492.4(CFTR):c.3454G>C (p.Asp1152His)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000492.4(CFTR):c.3454G>C (p.Asp1152His)
Variation ID: 35867 Accession: VCV000035867.68
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q31.2 7: 117614699 (GRCh38) [ NCBI UCSC ] 7: 117254753 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jun 28, 2015 Apr 15, 2024 Mar 24, 2021 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000492.4:c.3454G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000483.3:p.Asp1152His missense NC_000007.14:g.117614699G>C NC_000007.13:g.117254753G>C NG_016465.4:g.153916G>C LRG_663:g.153916G>C LRG_663t1:c.3454G>C LRG_663p1:p.Asp1152His P13569:p.Asp1152His - Protein change
- D1152H
- Other names
- -
- Canonical SPDI
- NC_000007.14:117614698:G:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00033
The Genome Aggregation Database (gnomAD), exomes 0.00040
Trans-Omics for Precision Medicine (TOPMed) 0.00038
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023
Exome Aggregation Consortium (ExAC) 0.00026
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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CFTR | - | - |
GRCh38 GRCh37 |
3598 | 4891 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (13) |
criteria provided, multiple submitters, no conflicts
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Jan 24, 2024 | RCV000046895.40 | |
Pathogenic/Likely pathogenic (13) |
criteria provided, multiple submitters, no conflicts
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Feb 1, 2024 | RCV000325638.45 | |
drug response (1) |
reviewed by expert panel
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Mar 24, 2021 | RCV000660854.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 29, 2018 | RCV001009365.9 | |
Pathogenic (1) |
criteria provided, single submitter
|
- | RCV001004498.9 | |
Pathogenic (1) |
no assertion criteria provided
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- | RCV001283745.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 13, 2018 | RCV001334484.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 16, 2022 | RCV001642237.10 | |
Pathogenic (2) |
no assertion criteria provided
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Aug 23, 2021 | RCV001826514.12 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 30, 2024 | RCV003398571.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 30, 2023 | RCV003473142.1 | |
click to load more click to collapse |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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drug response
(Mar 24, 2021)
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reviewed by expert panel
Method: curation
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ivacaftor response - Efficacy
Drug used for
Cystic Fibrosis
Affected status: yes
Allele origin:
germline
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PharmGKB
Accession: SCV000783093.2
First in ClinVar: Jul 09, 2018 Last updated: Dec 12, 2021 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Jul 05, 2017)
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criteria provided, single submitter
Method: research
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Cystic fibrosis
Affected status: unknown
Allele origin:
unknown,
maternal
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HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: CSER-HudsonAlpha
Accession: SCV000584083.1 First in ClinVar: Apr 22, 2017 Last updated: Apr 22, 2017 |
Observation 1:
Number of individuals with the variant: 1
Observation 2:
Number of individuals with the variant: 1
Observation 3:
Number of individuals with the variant: 1
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Pathogenic
(Jul 12, 2018)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000329250.6
First in ClinVar: Dec 06, 2016 Last updated: Apr 17, 2019 |
Comment:
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; … (more)
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. (less)
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Pathogenic
(Aug 22, 2018)
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criteria provided, single submitter
Method: clinical testing
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CFTR-Related Disorders
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000916188.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Congenital bilateral aplasia of vas deferens from CFTR mutation
Cystic fibrosis
Affected status: unknown
Allele origin:
germline
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Baylor Genetics
Accession: SCV001163543.1
First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020 |
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Pathogenic
(Oct 02, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001449991.1
First in ClinVar: Dec 10, 2020 Last updated: Dec 10, 2020 |
Number of individuals with the variant: 1
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Pathogenic
(Feb 13, 2018)
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criteria provided, single submitter
Method: clinical testing
|
Congenital bilateral aplasia of vas deferens from CFTR mutation
Affected status: yes
Allele origin:
paternal
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Baylor Genetics
Accession: SCV001527341.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
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, … (more)
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] (less)
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Pathogenic
(Oct 26, 2021)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: yes
Allele origin:
maternal
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Baylor Genetics
Study: CSER-TexasKidsCanSeq
Accession: SCV002030178.1 First in ClinVar: Dec 12, 2021 Last updated: Dec 12, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
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Pathogenic
(Aug 23, 2021)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: unknown
Allele origin:
germline
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Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002507338.1
First in ClinVar: May 16, 2022 Last updated: May 16, 2022 |
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Pathogenic
(Oct 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004183529.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Pathogenic
(Oct 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Bronchiectasis with or without elevated sweat chloride 1
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004211630.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Likely pathogenic
(Aug 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000601100.5
First in ClinVar: Mar 08, 2017 Last updated: Jan 06, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Mar 05, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002019233.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
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Pathogenic
(Oct 24, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000603066.8
First in ClinVar: Sep 30, 2017 Last updated: Feb 20, 2024 |
Comment:
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 … (more)
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. (less)
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Likely pathogenic
(Jan 30, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
CFTR-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004111459.2
First in ClinVar: Nov 20, 2023 Last updated: Mar 16, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Feb 01, 2024)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002586192.9
First in ClinVar: Oct 22, 2022 Last updated: Apr 15, 2024 |
Comment:
CFTR: PM3:Very Strong, PM2:Supporting, PS3:Supporting
Number of individuals with the variant: 4
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Pathogenic
(Oct 28, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000511351.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
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Pathogenic
(May 22, 2017)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000227775.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 8
Sex: mixed
|
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Pathogenic
(Jul 09, 2019)
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criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: unknown
Allele origin:
germline
|
Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV000996035.1
First in ClinVar: Oct 19, 2019 Last updated: Oct 19, 2019 |
|
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Pathogenic
(Jan 29, 2018)
|
criteria provided, single submitter
Method: curation
|
cystic fibrosis
CFTR-related disorders
Affected status: yes, no
Allele origin:
germline
|
CFTR-France
Accession: SCV001169218.1
First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020 |
Comment:
when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD
Observation 1:
Sex: mixed
Observation 2:
Sex: female
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Pathogenic
(Nov 11, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV001193906.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 03, 2020 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Jul 22, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV001810328.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Sex: mixed
|
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Pathogenic
(Mar 16, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Obstructive azoospermia
Affected status: yes
Allele origin:
germline
|
Institute of Reproductive Genetics, University of Münster
Accession: SCV001860330.2
First in ClinVar: Sep 19, 2021 Last updated: Mar 28, 2022 |
Number of individuals with the variant: 1
|
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Pathogenic
(Aug 04, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002502719.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: yes
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Pathogenic
(Jan 13, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV001181807.3
First in ClinVar: Mar 16, 2020 Last updated: Nov 29, 2022 |
Comment:
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 … (more)
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. (less)
Number of individuals with the variant: 1
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Pathogenic
(Nov 05, 2018)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: yes
Allele origin:
unknown
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Mendelics
Accession: SCV000886266.2
First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022 |
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Pathogenic
(Jan 24, 2024)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000074908.13
First in ClinVar: Jul 03, 2013 Last updated: Feb 28, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Jul 16, 2015)
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no assertion criteria provided
Method: clinical testing
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Cystic Fibrosis
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000052174.2
First in ClinVar: Apr 04, 2013 Last updated: Jun 28, 2015 |
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Pathogenic
(Nov 13, 2015)
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no assertion criteria provided
Method: research
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Cystic fibrosis
Affected status: unknown
Allele origin:
germline
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Division of Human Genetics, Children's Hospital of Philadelphia
Study: CSER-PediSeq
Accession: SCV000536841.1 First in ClinVar: Apr 22, 2017 Last updated: Apr 22, 2017 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001808839.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001953101.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001973888.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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Pathogenic
(Aug 23, 2021)
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no assertion criteria provided
Method: clinical testing
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CFTR-related disorders
Affected status: unknown
Allele origin:
germline
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Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002507422.1
First in ClinVar: May 16, 2022 Last updated: May 16, 2022 |
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Pathogenic
(-)
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no assertion criteria provided
Method: provider interpretation
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Male infertility
Affected status: yes
Allele origin:
germline
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MAGI's Lab - Research, MAGI Group
Accession: SCV001432688.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001963164.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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Pathogenic
(Mar 21, 2018)
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no assertion criteria provided
Method: clinical testing
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CFTR-related disorders
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002075827.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Screening by single-molecule molecular inversion probes targeted sequencing panel of candidate genes of infertility in azoospermic infertile Jordanian males. | Batiha O | Human fertility (Cambridge, England) | 2022 | PMID: 34190021 |
The genetic structure of the Turkish population reveals high levels of variation and admixture. | Kars ME | Proceedings of the National Academy of Sciences of the United States of America | 2021 | PMID: 34426522 |
Male Infertility Diagnosis: Improvement of Genetic Analysis Performance by the Introduction of Pre-Diagnostic Genes in a Next-Generation Sequencing Custom-Made Panel. | Precone V | Frontiers in endocrinology | 2021 | DOI: 10.3389/fendo.2020.605237 |
Male Infertility Diagnosis: Improvement of Genetic Analysis Performance by the Introduction of Pre-Diagnostic Genes in a Next-Generation Sequencing Custom-Made Panel. | Precone V | Frontiers in endocrinology | 2021 | PMID: 33574797 |
The CFTR Mutation c.3453G > C (D1152H) Confers an Anion Selectivity Defect in Primary Airway Tissue that Can Be Rescued by Ivacaftor. | Laselva O | Journal of personalized medicine | 2020 | PMID: 32414100 |
Sequencing as a first-line methodology for cystic fibrosis carrier screening. | Beauchamp KA | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 31036917 |
Comprehensive genetic study of cystic fibrosis in Slovak patients in 25 years of genetic diagnostics. | Soltysova A | The clinical respiratory journal | 2018 | PMID: 28544683 |
CFTR-France, a national relational patient database for sharing genetic and phenotypic data associated with rare CFTR variants. | Claustres M | Human mutation | 2017 | PMID: 28603918 |
Applying Cystic Fibrosis Transmembrane Conductance Regulator Genetics and CFTR2 Data to Facilitate Diagnoses. | Sosnay PR | The Journal of pediatrics | 2017 | PMID: 28129809 |
Genotype-phenotype correlation and functional studies in patients with cystic fibrosis bearing CFTR complex alleles. | Terlizzi V | Journal of medical genetics | 2017 | PMID: 27738188 |
Changes of CFTR functional measurements and clinical improvements in cystic fibrosis patients with non p.Gly551Asp gating mutations treated with ivacaftor. | Mesbahi M | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2017 | PMID: 27659740 |
Sweat chloride and immunoreactive trypsinogen in infants carrying two CFTR mutations and not affected by cystic fibrosis. | Castellani C | Archives of disease in childhood | 2017 | PMID: 26755536 |
Molecular Genetics of Cystic Fibrosis Transmembrane Conductance Regulator: Genotype and Phenotype. | Sosnay PR | Pediatric clinics of North America | 2016 | PMID: 27469177 |
Benign and Deleterious Cystic Fibrosis Transmembrane Conductance Regulator Mutations Identified by Sequencing in Positive Cystic Fibrosis Newborn Screen Children from California. | Salinas DB | PloS one | 2016 | PMID: 27214204 |
Genophenotypic Analysis of Pediatric Patients With Acute Recurrent and Chronic Pancreatitis. | Palermo JJ | Pancreas | 2016 | PMID: 27171515 |
CFTR and/or pancreatitis susceptibility genes mutations as risk factors of pancreatitis in cystic fibrosis patients? | Gaitch N | Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] | 2016 | PMID: 27086061 |
NGS-Based Assay for the Identification of Individuals Carrying Recessive Genetic Mutations in Reproductive Medicine. | Abulí A | Human mutation | 2016 | PMID: 26990548 |
Non-allergic asthma as a CFTR-related disorder. | Schulz A | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2016 | PMID: 26526220 |
A Genotypic-Oriented View of CFTR Genetics Highlights Specific Mutational Patterns Underlying Clinical Macrocategories of Cystic Fibrosis. | Lucarelli M | Molecular medicine (Cambridge, Mass.) | 2015 | PMID: 25910067 |
Clinical expression of patients with the D1152H CFTR mutation. | Terlizzi V | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2015 | PMID: 25583415 |
Analysis of cystic fibrosis gene mutations in children with cystic fibrosis and in 964 infertile couples within the region of Basilicata, Italy: a research study. | Dell'Edera D | Journal of medical case reports | 2014 | PMID: 25304080 |
Pathogenic variants for Mendelian and complex traits in exomes of 6,517 European and African Americans: implications for the return of incidental results. | Tabor HK | American journal of human genetics | 2014 | PMID: 25087612 |
Mechanisms of CFTR functional variants that impair regulated bicarbonate permeation and increase risk for pancreatitis but not for cystic fibrosis. | LaRusch J | PLoS genetics | 2014 | PMID: 25033378 |
Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. | Van Goor F | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2014 | PMID: 23891399 |
Personalized genomic disease risk of volunteers. | Gonzalez-Garay ML | Proceedings of the National Academy of Sciences of the United States of America | 2013 | PMID: 24082139 |
Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. | Sosnay PR | Nature genetics | 2013 | PMID: 23974870 |
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. | Masson E | PloS one | 2013 | PMID: 23951356 |
An empirical estimate of carrier frequencies for 400+ causal Mendelian variants: results from an ethnically diverse clinical sample of 23,453 individuals. | Lazarin GA | Genetics in medicine : official journal of the American College of Medical Genetics | 2013 | PMID: 22975760 |
Measurements of CFTR-mediated Cl- secretion in human rectal biopsies constitute a robust biomarker for Cystic Fibrosis diagnosis and prognosis. | Sousa M | PloS one | 2012 | PMID: 23082198 |
A large deletion causes apparent homozygosity for the D1152H mutation in the cystic fibrosis transmembrane regulator (CFTR) gene. | Diana A | Gene | 2012 | PMID: 22310382 |
Extensive molecular analysis of patients bearing CFTR-related disorders. | Amato F | The Journal of molecular diagnostics : JMD | 2012 | PMID: 22020151 |
The D1152H cystic fibrosis mutation in prenatal carrier screening, patients and prenatal diagnosis. | Peleg L | Journal of medical screening | 2011 | PMID: 22156145 |
Enhanced frequency of CFTR gene variants in couples who are candidates for assisted reproductive technology treatment. | Tomaiuolo R | Clinical chemistry and laboratory medicine | 2011 | PMID: 21679131 |
Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. | Steiner B | Human mutation | 2011 | PMID: 21520337 |
CFTR allelic heterogeneity in Mexican patients with cystic fibrosis: implications for molecular screening. | Chávez-Saldaña M | Revista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion | 2010 | PMID: 21416780 |
CFTR gene mutation in patients with apparently idiopathic pancreatitis: lack of phenotype-genotype correlation. | Pelletier AL | Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] | 2010 | PMID: 20460946 |
Non-classic cystic fibrosis associated with D1152H CFTR mutation. | Burgel PR | Clinical genetics | 2010 | PMID: 19843100 |
Cystic fibrosis transmembrane conductance regulator mutations in azoospermic and oligospermic men and their partners. | Gallati S | Reproductive biomedicine online | 2009 | PMID: 20021716 |
[The diagnosis of cystic fibrosis in adults: lessons from a family story]. | Coman T | Revue des maladies respiratoires | 2009 | PMID: 19212293 |
Cystic fibrosis in a boy with meconium ileus and mild clinical phenotype associated with 2183AA-G/D1152H genotype. | Yalçin E | The Turkish journal of pediatrics | 2008 | PMID: 19014055 |
Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice. | Castellani C | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2008 | PMID: 18456578 |
The changing face of the exocrine pancreas in cystic fibrosis: the correlation between pancreatic status, pancreatitis and cystic fibrosis genotype. | Augarten A | European journal of gastroenterology & hepatology | 2008 | PMID: 18301294 |
Genetic cystic fibrosis transmembrane regulator 4016insT D1152H compound heterozygosity and male infertility: an Italian case report. | Rocchetti S | Clinical chemistry and laboratory medicine | 2007 | PMID: 17617039 |
Does cystic fibrosis neonatal screening detect atypical CF forms? Extended genetic characterization and 4-year clinical follow-up. | Narzi L | Clinical genetics | 2007 | PMID: 17594398 |
Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. | Keiles S | Pancreas | 2006 | PMID: 17003641 |
Cystic fibrosis mutations with widely variable phenotype: the D1152H example. | Mussaffi H | Pediatric pulmonology | 2006 | PMID: 16429425 |
Complete cystic fibrosis transmembrane conductance regulator gene sequencing in patients with idiopathic chronic pancreatitis and controls. | Weiss FU | Gut | 2005 | PMID: 15987793 |
A CFTR mutation (D1152H) in a family with mild lung disease and normal sweat chlorides. | Highsmith WE Jr | Clinical genetics | 2005 | PMID: 15952991 |
Diagnostic testing by CFTR gene mutation analysis in a large group of Hispanics: novel mutations and assessment of a population-specific mutation spectrum. | Schrijver I | The Journal of molecular diagnostics : JMD | 2005 | PMID: 15858154 |
Mutations of the CFTR gene in Turkish patients with congenital bilateral absence of the vas deferens. | Dayangaç D | Human reproduction (Oxford, England) | 2004 | PMID: 15070876 |
Hyperechogenic bowel loops and meconium ileus in a fetus carrying the D1152H and G542X cystic fibrosis CFTR mutations. | Orgad S | Prenatal diagnosis | 2002 | PMID: 12124706 |
Genetic and clinical features of false-negative infants in a neonatal screening programme for cystic fibrosis. | Padoan R | Acta paediatrica (Oslo, Norway : 1992) | 2002 | PMID: 11883825 |
[Cystic fibrosis and normal sweat chloride values: a case-report]. | Lebecque P | Revue des maladies respiratoires | 2001 | PMID: 11547256 |
European Epidemiologic Registry of Cystic Fibrosis (ERCF): comparison of major disease manifestations between patients with different classes of mutations. | Koch C | Pediatric pulmonology | 2001 | PMID: 11180668 |
Characterization of mutations located in exon 18 of the CFTR gene. | Vankeerberghen A | FEBS letters | 1998 | PMID: 9804160 |
Mutations in the cystic fibrosis gene in patients with congenital absence of the vas deferens. | Chillón M | The New England journal of medicine | 1995 | PMID: 7739684 |
Mild course of cystic fibrosis in an adult with the D1152H mutation. | Feldmann D | Clinical chemistry | 1995 | PMID: 7586569 |
http://www.cftr2.org/ | - | - | - | - |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CFTR | - | - | - | - |
https://www.pharmgkb.org/clinicalAnnotation/1449191758 | - | - | - | - |
https://www.pharmgkb.org/variant/PA166164958 | - | - | - | - |
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Text-mined citations for rs75541969 ...
HelpRecord last updated Apr 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.