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.
ClinVar Genomic variation as it relates to human health
NM_000492.4(CFTR):c.328G>C (p.Asp110His)
Germline
Top reviewed classifications are shown here.
Submission summary:
Reviewed by expert panel
Pathogenic
Mar 2017 by
CFTR2
for
Cystic fibrosis
Drug response
Mar 2021 by
PharmGKB
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000492.4(CFTR):c.328G>C (p.Asp110His)
Variation ID: 7108 Accession: VCV000007108.27
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 7q31.2 7: 117530953 (GRCh38) [ NCBI UCSC ] 7: 117171007 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Oct 22, 2013 Jun 17, 2024 Mar 24, 2021 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000492.4:c.328G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000483.3:p.Asp110His missense NC_000007.14:g.117530953G>C NC_000007.13:g.117171007G>C NG_016465.4:g.70170G>C LRG_663:g.70170G>C LRG_663t1:c.328G>C LRG_663p1:p.Asp110His P13569:p.Asp110His - Protein change
- D110H
- Other names
- -
- Canonical SPDI
- NC_000007.14:117530952:G:C
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| CFTR | - | - |
GRCh38 GRCh37 |
3826 | 5201 | |
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. |
|---|---|---|---|---|
| Pathogenic (9) |
reviewed by expert panel
|
Mar 17, 2017 | RCV000007527.26 | |
| not provided (1) |
no classification provided
|
- | RCV000058930.2 | |
| drug response (1) |
reviewed by expert panel
|
Mar 24, 2021 | RCV000660769.5 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Nov 20, 2017 | RCV000780153.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
- | RCV001004427.2 | |
|
CFTR-related disorder
|
Pathogenic (1) |
criteria provided, single submitter
|
Jan 29, 2018 | RCV001009392.2 |
| Pathogenic (1) |
criteria provided, single submitter
|
May 4, 2022 | RCV002247259.1 | |
|
CFTR-related disorder
|
Pathogenic (2) |
no assertion criteria provided
|
Aug 20, 2019 | RCV001835624.5 |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 22, 2024 | RCV003473000.2 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Mar 17, 2017)
|
reviewed by expert panel
Method: research
|
Cystic fibrosis
Affected status: yes
Allele origin:
germline
|
CFTR2
Study: CFTR2
Accession: SCV000071497.4 First in ClinVar: Oct 18, 2013 Last updated: Jan 06, 2018 |
|
|
|
drug response
Drug-variant association: Efficacy
(Mar 24, 2021)
|
reviewed by expert panel
Method: curation
|
ivacaftor response - Efficacy
Drug used for
Cystic Fibrosis
Affected status: yes
Allele origin:
germline
|
PharmGKB
Accession: SCV000783008.2
First in ClinVar: Jul 09, 2018 Last updated: Dec 12, 2021
Comment:
Drug is not necessarily used to treat response condition
|
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)
|
|
|
Pathogenic
(Nov 20, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000917200.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: The CFTR c.328G>C (p.Asp110His) variant involves the alteration of a conserved nucleotide that is located in the ABC transporter type 1, transmembrane domain … (more)
Variant summary: The CFTR c.328G>C (p.Asp110His) variant involves the alteration of a conserved nucleotide that is located in the ABC transporter type 1, transmembrane domain (InterPro). 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 5/245956 control chromosomes at a frequency of 0.0000203, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). Compound heterozygotes and homozygotes for this variant have been found in numerous patients with CBAVD, CF, and in pt with clinical findings suggestive of CF. A functional study showed that baseline chloride transport in CFTR-D110H transfected FRT cells was 9.1% of that in WT-CFTR transfected FRT cells (Van Goor_2013), indicating that D110H significantly affects normal function of CFTR. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
|
|
|
Likely pathogenic
(Dec 05, 2014)
|
criteria provided, single submitter
Method: literature only
|
Cystic fibrosis
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000220934.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
|
|
|
Pathogenic
(Jan 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001589600.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 110 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 110 of the CFTR protein (p.Asp110His). This variant is present in population databases (rs113993958, gnomAD 0.004%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 2344617, 9272157, 18373402, 19897426, 20059485, 20949073, 22724884, 23974870). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 7108). 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: 11278813, 23891399). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Congenital bilateral aplasia of vas deferens from CFTR mutation
Cystic fibrosis
Affected status: unknown
Allele origin:
germline
|
Baylor Genetics
Accession: SCV001163471.1
First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020 |
|
|
|
Pathogenic
(Jan 29, 2018)
|
criteria provided, single submitter
Method: curation
|
cystic fibrosis
CFTR-related disorders
Affected status: yes
Allele origin:
germline
|
CFTR-France
Accession: SCV001169245.1
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
|
|
|
Pathogenic
(Jul 22, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV001810353.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Sex: mixed
|
|
|
Pathogenic
(Aug 20, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: unknown
Allele origin:
germline
|
Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002507327.1
First in ClinVar: May 16, 2022 Last updated: May 16, 2022 |
|
|
|
Pathogenic
(May 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary pancreatitis
Affected status: unknown
Allele origin:
germline
|
Mendelics
Accession: SCV002518665.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
|
|
|
Pathogenic
(Dec 27, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: unknown
Allele origin:
germline
|
Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV003839089.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
Comment:
Disease-causing CFTR variant. See www.CFTR2.org for phenotype information.
|
|
|
Pathogenic
(Oct 02, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV002573987.3
First in ClinVar: Sep 24, 2022 Last updated: Feb 14, 2024 |
Comment:
Criteria applied: PM5_STR,PS3_MOD,PM1,PM3,PM2_SUP,PP3
Clinical Features:
Dysphagia (present) , Microcephaly (present) , Failure to thrive (present) , Metabolic alkalosis (present) , Moderate global developmental delay (present)
Sex: male
|
|
|
Pathogenic
(Apr 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002611948.3
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.D110H pathogenic mutation (also known as c.328G>C), located in coding exon 4 of the CFTR gene, results from a G to C substitution at … (more)
The p.D110H pathogenic mutation (also known as c.328G>C), located in coding exon 4 of the CFTR gene, results from a G to C substitution at nucleotide position 328. The aspartic acid at codon 110 is replaced by histidine, an amino acid with similar properties. This mutation was first described in a child with elevated sweat chloride levels and p.F508del confirmed in trans (Dean M et al. Cell, 1990 Jun;61:863-70). Another study described a homozygous Turkish male who presented with congenital bilateral absence of the vas deferens (CBAVD), asthma bronchiale, and obstipation (Dörk T et al. Hum. Genet., 1997 Sep;100:365-77). Functional data showed a reduced level of CFTR protein and 9% chloride activity compared to wild type (Van Goor F et al. J. Cyst. Fibros., 2014 Jan;13:29-36). Another study suggested that this mutation disrupts the chloride channel activity by destabilizing the open state of the CFTR protein (Hämmerle MM et al. J. Biol. Chem., 2001 May;276:14848-54). In addition, this mutation is associated with pancreatic sufficiency (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). An alteration at the same amino acid position, p.D110E, was also described in a child with elevated sweat chloride levels and pancreatic sufficiency (Padoan R et al. Hum. Mutat., 2000 May;15:485). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
|
|
|
Pathogenic
(Mar 22, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Bronchiectasis with or without elevated sweat chloride 1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004213308.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Jan 01, 1991)
|
no assertion criteria provided
Method: literature only
|
CYSTIC FIBROSIS
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000027728.3
First in ClinVar: Apr 04, 2013 Last updated: Apr 12, 2018 |
Comment on evidence:
Using the method for identifying single-strand conformation polymorphisms (SSCPs) developed by Orita et al. (1989), Dean et al. (1990) identified 3 different mutations associated with … (more)
Using the method for identifying single-strand conformation polymorphisms (SSCPs) developed by Orita et al. (1989), Dean et al. (1990) identified 3 different mutations associated with mild cystic fibrosis (CF; 219700). All 3 mutations replaced charged amino acids with less polar residues and resulted in changes in the putative transmembrane sections of the molecule. The mutated amino acids were found to be ones conserved in both rodents and amphibians and to lie in a region of CFTR that is believed to form a channel in the membrane. In a family identified as BOS-7, a C-to-G transversion in exon 4 replaced an aspartic acid residue with histidine (D110H). (The Orita method for identifying SSCPs involves amplification of 100-400 bp segments of radiolabeled DNA, which are subsequently denatured and electrophoresed on high resolution, nondenaturing acrylamide gels. Under these conditions each strand of the DNA fragment can fold back on itself in a unique conformation. Mutations within a DNA segment will often alter the secondary structure of the molecule and affect its electrophoretic mobility.) (less)
|
|
|
Pathogenic
(Mar 17, 2017)
|
no assertion criteria provided
Method: clinical testing
|
CFTR-related disorders
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002080120.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
|
|
|
Pathogenic
(Aug 20, 2019)
|
no assertion criteria provided
Method: clinical testing
|
CFTR-related disorders
Affected status: unknown
Allele origin:
germline
|
Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002507411.1
First in ClinVar: May 16, 2022 Last updated: May 16, 2022 |
|
|
|
not provided
(-)
|
no classification provided
Method: not provided
|
not provided
Affected status: not provided
Allele origin:
germline
|
SNPedia
Accession: SCV000090451.1
First in ClinVar: Oct 22, 2013 Last updated: Oct 22, 2013 |
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
Variant summary: The CFTR c.328G>C (p.Asp110His) variant involves the alteration of a conserved nucleotide that is located in the ABC transporter type 1, transmembrane domain (InterPro). 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 5/245956 control chromosomes at a frequency of 0.0000203, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). Compound heterozygotes and homozygotes for this variant have been found in numerous patients with CBAVD, CF, and in pt with clinical findings suggestive of CF. A functional study showed that baseline chloride transport in CFTR-D110H transfected FRT cells was 9.1% of that in WT-CFTR transfected FRT cells (Van Goor_2013), indicating that D110H significantly affects normal function of CFTR. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 110 of the CFTR protein (p.Asp110His). This variant is present in population databases (rs113993958, gnomAD 0.004%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 2344617, 9272157, 18373402, 19897426, 20059485, 20949073, 22724884, 23974870). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 7108). 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: 11278813, 23891399). For these reasons, this variant has been classified as Pathogenic.
Comment:
when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD
Comment:
Disease-causing CFTR variant. See www.CFTR2.org for phenotype information.
Comment:
Criteria applied: PM5_STR,PS3_MOD,PM1,PM3,PM2_SUP,PP3
Comment:
The p.D110H pathogenic mutation (also known as c.328G>C), located in coding exon 4 of the CFTR gene, results from a G to C substitution at nucleotide position 328. The aspartic acid at codon 110 is replaced by histidine, an amino acid with similar properties. This mutation was first described in a child with elevated sweat chloride levels and p.F508del confirmed in trans (Dean M et al. Cell, 1990 Jun;61:863-70). Another study described a homozygous Turkish male who presented with congenital bilateral absence of the vas deferens (CBAVD), asthma bronchiale, and obstipation (Dörk T et al. Hum. Genet., 1997 Sep;100:365-77). Functional data showed a reduced level of CFTR protein and 9% chloride activity compared to wild type (Van Goor F et al. J. Cyst. Fibros., 2014 Jan;13:29-36). Another study suggested that this mutation disrupts the chloride channel activity by destabilizing the open state of the CFTR protein (Hämmerle MM et al. J. Biol. Chem., 2001 May;276:14848-54). In addition, this mutation is associated with pancreatic sufficiency (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). An alteration at the same amino acid position, p.D110E, was also described in a child with elevated sweat chloride levels and pancreatic sufficiency (Padoan R et al. Hum. Mutat., 2000 May;15:485). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
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. |
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 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.
Comment:
Variant summary: The CFTR c.328G>C (p.Asp110His) variant involves the alteration of a conserved nucleotide that is located in the ABC transporter type 1, transmembrane domain (InterPro). 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 5/245956 control chromosomes at a frequency of 0.0000203, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). Compound heterozygotes and homozygotes for this variant have been found in numerous patients with CBAVD, CF, and in pt with clinical findings suggestive of CF. A functional study showed that baseline chloride transport in CFTR-D110H transfected FRT cells was 9.1% of that in WT-CFTR transfected FRT cells (Van Goor_2013), indicating that D110H significantly affects normal function of CFTR. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 110 of the CFTR protein (p.Asp110His). This variant is present in population databases (rs113993958, gnomAD 0.004%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 2344617, 9272157, 18373402, 19897426, 20059485, 20949073, 22724884, 23974870). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 7108). 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: 11278813, 23891399). For these reasons, this variant has been classified as Pathogenic.
Comment:
when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD
Comment:
Disease-causing CFTR variant. See www.CFTR2.org for phenotype information.
Comment:
Criteria applied: PM5_STR,PS3_MOD,PM1,PM3,PM2_SUP,PP3
Comment:
The p.D110H pathogenic mutation (also known as c.328G>C), located in coding exon 4 of the CFTR gene, results from a G to C substitution at nucleotide position 328. The aspartic acid at codon 110 is replaced by histidine, an amino acid with similar properties. This mutation was first described in a child with elevated sweat chloride levels and p.F508del confirmed in trans (Dean M et al. Cell, 1990 Jun;61:863-70). Another study described a homozygous Turkish male who presented with congenital bilateral absence of the vas deferens (CBAVD), asthma bronchiale, and obstipation (Dörk T et al. Hum. Genet., 1997 Sep;100:365-77). Functional data showed a reduced level of CFTR protein and 9% chloride activity compared to wild type (Van Goor F et al. J. Cyst. Fibros., 2014 Jan;13:29-36). Another study suggested that this mutation disrupts the chloride channel activity by destabilizing the open state of the CFTR protein (Hämmerle MM et al. J. Biol. Chem., 2001 May;276:14848-54). In addition, this mutation is associated with pancreatic sufficiency (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). An alteration at the same amino acid position, p.D110E, was also described in a child with elevated sweat chloride levels and pancreatic sufficiency (Padoan R et al. Hum. Mutat., 2000 May;15:485). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Three charged amino acids in extracellular loop 1 are involved in maintaining the outer pore architecture of CFTR. | Cui G | The Journal of general physiology | 2014 | PMID: 25024266 |
| 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 |
| Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. | Sosnay PR | Nature genetics | 2013 | PMID: 23974870 |
| Screening for F508del as a first step in the molecular diagnosis of cystic fibrosis. | Marson FA | Jornal brasileiro de pneumologia : publicacao oficial da Sociedade Brasileira de Pneumologia e Tisilogia | 2013 | PMID: 23857699 |
| Combined computational-experimental analyses of CFTR exon strength uncover predictability of exon-skipping level. | Aissat A | Human mutation | 2013 | PMID: 23420618 |
| Distribution of CFTR mutations in the Czech population: positive impact of integrated clinical and laboratory expertise, detection of novel/de novo alleles and relevance for related/derived populations. | Křenková P | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2013 | PMID: 23276700 |
| Mid-trimester hyperechogenic bowel in a fetus of Turkish origin carrying a rarely seen mutation of cystic fibrosis. | Kazandi M | Archives of Iranian medicine | 2012 | PMID: 22724884 |
| Comparing the American and European diagnostic guidelines for cystic fibrosis: same disease, different language? | Ooi CY | Thorax | 2012 | PMID: 22504961 |
| Newborn screening for cystic fibrosis in Alberta: Two years of experience. | Lilley M | Paediatrics & child health | 2010 | PMID: 22043142 |
| Alternative splicing at a NAGNAG acceptor site as a novel phenotype modifier. | Hinzpeter A | PLoS genetics | 2010 | PMID: 20949073 |
| Do common in silico tools predict the clinical consequences of amino-acid substitutions in the CFTR gene? | Dorfman R | Clinical genetics | 2010 | PMID: 20059485 |
| A 10-year large-scale cystic fibrosis carrier screening in the Italian population. | Picci L | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2010 | PMID: 19897426 |
| 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 |
| CFTR mutations in Turkish and North African cystic fibrosis patients in Europe: implications for screening. | Lakeman P | Genetic testing | 2008 | PMID: 18373402 |
| A haplotype framework for cystic fibrosis mutations in Iran. | Elahi E | The Journal of molecular diagnostics : JMD | 2006 | PMID: 16436643 |
| Comprehensive cystic fibrosis mutation epidemiology and haplotype characterization in a southern Italian population. | Castaldo G | Annals of human genetics | 2005 | PMID: 15638824 |
| Genotype-phenotype correlation and frequency of the 3199del6 cystic fibrosis mutation among I148T carriers: results from a collaborative study. | Monaghan KG | Genetics in medicine : official journal of the American College of Medical Genetics | 2004 | PMID: 15371907 |
| Molecular analysis using DHPLC of cystic fibrosis: increase of the mutation detection rate among the affected population in Central Italy. | D'Apice MR | BMC medical genetics | 2004 | PMID: 15084222 |
| Cystic fibrosis in Greece: molecular diagnosis, haplotypes, prenatal diagnosis and carrier identification amongst high-risk individuals. | Kanavakis E | Clinical genetics | 2003 | PMID: 12752573 |
| Highest heterogeneity for cystic fibrosis: 36 mutations account for 75% of all CF chromosomes in Turkish patients. | Kilinç MO | American journal of medical genetics | 2002 | PMID: 12439892 |
| Cystic fibrosis mutations and associated haplotypes in Turkish cystic fibrosis patients. | Onay T | Human biology | 2001 | PMID: 11446424 |
| Disease-associated mutations in the extracytoplasmic loops of cystic fibrosis transmembrane conductance regulator do not impede biosynthetic processing but impair chloride channel stability. | Hämmerle MM | The Journal of biological chemistry | 2001 | PMID: 11278813 |
| A novel missense mutation (D110E) in exon 4 of CFTR (ABCC7) in a CF infant presenting with hypochloraemic metabolic alkalosis. | Padoan R | Human mutation | 2000 | PMID: 10790222 |
| [Turkish infant with hypoelectrolytemia and metabolic alkalosis as the sole manifestations of a mild form of cystic fibrosis (mutation D110H)]. | Weller F | Klinische Padiatrie | 2000 | PMID: 10719683 |
| Analysis of the CFTR gene in Turkish cystic fibrosis patients: identification of three novel mutations (3172delAC, P1013L and M1028I). | Onay T | Human genetics | 1998 | PMID: 9521595 |
| Distinct spectrum of CFTR gene mutations in congenital absence of vas deferens. | Dörk T | Human genetics | 1997 | PMID: 9272157 |
| Genetic determination of exocrine pancreatic function in cystic fibrosis. | Kristidis P | American journal of human genetics | 1992 | PMID: 1376016 |
| Hereditary disorders in Saguenay-Lac-St-Jean (Quebec, Canada). | De Braekeleer M | Human heredity | 1991 | PMID: 1937486 |
| Multiple mutations in highly conserved residues are found in mildly affected cystic fibrosis patients. | Dean M | Cell | 1990 | PMID: 2344617 |
| Detection of polymorphisms of human DNA by gel electrophoresis as single-strand conformation polymorphisms. | Orita M | Proceedings of the National Academy of Sciences of the United States of America | 1989 | PMID: 2565038 |
| https://cftr2.org | - | - | - | - |
| https://www.pharmgkb.org/clinicalAnnotation/1449191407 | - | - | - | - |
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Text-mined citations for rs113993958 ...
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Record last updated Sep 29, 2024
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