ClinVar Genomic variation as it relates to human health
NM_000492.4(CFTR):c.3873G>C (p.Gln1291His)
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.3873G>C (p.Gln1291His)
Variation ID: 7152 Accession: VCV000007152.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q31.2 7: 117642593 (GRCh38) [ NCBI UCSC ] 7: 117282647 (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 Apr 12, 2018 May 1, 2024 Jul 8, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000492.4:c.3873G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000483.3:p.Gln1291His missense NC_000007.14:g.117642593G>C NC_000007.13:g.117282647G>C NG_016465.4:g.181810G>C LRG_663:g.181810G>C LRG_663t1:c.3873G>C LRG_663p1:p.Gln1291His P13569:p.Gln1291His - Protein change
- Q1291H
- Other names
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- Canonical SPDI
- NC_000007.14:117642592: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
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The frequency of the allele represented by this VCV record.
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Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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 |
3941 | 5359 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Jul 8, 2023 | RCV000007572.16 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 7, 2018 | RCV000780123.1 | |
Likely pathogenic (1) |
no assertion criteria provided
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Mar 2, 2020 | RCV002228016.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jul 1, 2023 | RCV003473024.1 |
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
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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
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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
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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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Likely pathogenic
(Jul 08, 2023)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001574473.4
First in ClinVar: May 10, 2021 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 1291 of the CFTR protein (p.Gln1291His). … (more)
This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 1291 of the CFTR protein (p.Gln1291His). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs121909015, gnomAD 0.002%). This missense change has been observed in individuals with clinical features of CFTR-related conditions (PMID: 1284466, 7551394, 21388895, 22423042). ClinVar contains an entry for this variant (Variation ID: 7152). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CFTR function (PMID: 31127727). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in activation of a cryptic splice site in the intron and introduces a premature termination codon (PMID: 1284466). The resulting mRNA is expected to undergo nonsense-mediated decay. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
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Pathogenic
(Apr 29, 2020)
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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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Ambry Genetics
Accession: SCV002622435.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.3873G>C pathogenic mutation (also known as p.Q1291H), located in coding exon 23 of the CFTR gene, results from a G to C substitution at … (more)
The c.3873G>C pathogenic mutation (also known as p.Q1291H), located in coding exon 23 of the CFTR gene, results from a G to C substitution at nucleotide position 3873. The amino acid change results in glutamine to histidine at codon 1291, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 23, which makes it likely to have some effect on normal mRNA splicing. Analysis of a biopsy from a pancreatic sufficient individual with mild lung symptoms who was compound heterozygous for p.Q1291H demonstrated normal and aberrant splicing resulting from use of a cryptic site leading to the inclusion of 29 nucleotides in the intron and a predicted premature stop codon (Jones CT et al. Hum. Mol. Genet., 1992 Apr;1:11-7). In addition, this mutation has been reported in several individuals with elevated sweat chloride levels in conjunction with another pathogenic CFTR variant (Jones CT et al. Hum. Mol. Genet., 1992 Apr;1:11-7; Gilfillan A et al. J. Med. Genet., 1998 Feb;35:122-5; Baker MW et al. J. Cyst. Fibros., 2011 Jul;10:278-81) and has been reported as a variant of varying clinical consequences (VVCC) (Sosnay PR et al. Pediatr. Clin. North Am., 2016 08;63:585-98; The Clinical and Functional TRanslation of CFTR (CFTR2); available at http://cftr2.org. Accessed April 29, 2020). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Sep 07, 2018)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000917167.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: CFTR c.3873G>C (p.Gln1291His) results in a non-conservative amino acid change in the encoded protein sequence. The variant also alters a conserved nucleotide located … (more)
Variant summary: CFTR c.3873G>C (p.Gln1291His) results in a non-conservative amino acid change in the encoded protein sequence. The variant also alters a conserved nucleotide located to the last nucleotide of exon 20, affecting a canonical splice site and therefore could alter mRNA splicing, leading to a significantly altered protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: 4/5 predict the variant weakens a 5' splicing donor site. At least one publication reported experimental evidence that the variant resulted in both a 'correct' (although altered) splice product, and an incorrectly spliced mRNA from the use of a nearby cryptic splice site (29 bases into the adjacent intron), where the inclusion of the intronic sequence resulted in an in-frame, downstream stop codon (Jones1992). Another functional study demonstrated that the Gln1291His variant protein showed normal processing and trafficking to the plasma membrane, as well as unaltered single channel gating properties in the presence of ATP; however the data suggested the disruption of adenylate kinase-dependent gating that might affect channel activity in airway epithelia (Dong 2015). The variant allele was found at a frequency of 8.1e-06 in 245448 control chromosomes (gnomAD and publications). The variant, c.3873G>C, has been reported in the literature in multiple individuals affected with Cystic Fibrosis (Jones 1992, Dorfman 2010, Baker 2011). These data indicate that the variant is very likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Mar 02, 2020)
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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: SCV002507361.1
First in ClinVar: May 16, 2022 Last updated: May 16, 2022 |
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Likely pathogenic
(Jul 01, 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: SCV004213477.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Apr 01, 1992)
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no assertion criteria provided
Method: literature only
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CYSTIC FIBROSIS
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000027773.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 12, 2018 |
Comment on evidence:
In a patient with cystic fibrosis (CF; 219700), Jones et al. (1992) demonstrated a Q1291H mutation caused by a G-to-C transversion at the last nucleotide … (more)
In a patient with cystic fibrosis (CF; 219700), Jones et al. (1992) demonstrated a Q1291H mutation caused by a G-to-C transversion at the last nucleotide of exon 20 using the chemical cleavage mismatch technique. Further study, involving RNA-based PCR, demonstrated that the Q1291H is also a splice mutation. Both correctly and aberrantly spliced mRNAs were produced by the Q1291H allele. The incorrectly spliced product resulted from the use of a nearby cryptic splice site 29 bases into the adjacent intron. (less)
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Likely pathogenic
(Mar 02, 2020)
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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: SCV002507445.1
First in ClinVar: May 16, 2022 Last updated: May 16, 2022 |
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Uncertain significance
(Jan 03, 2017)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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Cystic fibrosis
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000800485.1
First in ClinVar: Apr 12, 2018 Last updated: Apr 12, 2018 |
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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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Panel-Based Exome Sequencing for Neuromuscular Disorders as a Diagnostic Service. | Westra D | Journal of neuromuscular diseases | 2019 | PMID: 31127727 |
Mutating the Conserved Q-loop Glutamine 1291 Selectively Disrupts Adenylate Kinase-dependent Channel Gating of the ATP-binding Cassette (ABC) Adenylate Kinase Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) and Reduces Channel Function in Primary Human Airway Epithelia. | Dong Q | The Journal of biological chemistry | 2015 | PMID: 25887396 |
Role of cystic fibrosis transmembrane conductance regulator in patients with chronic sinopulmonary disease. | Gonska T | Chest | 2012 | PMID: 22423042 |
Optimal DNA tier for the IRT/DNA algorithm determined by CFTR mutation results over 14 years of newborn screening. | Baker MW | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2011 | PMID: 21388895 |
Do common in silico tools predict the clinical consequences of amino-acid substitutions in the CFTR gene? | Dorfman R | Clinical genetics | 2010 | PMID: 20059485 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Mutations that change the position of the putative gamma-phosphate linker in the nucleotide binding domains of CFTR alter channel gating. | Berger AL | The Journal of biological chemistry | 2002 | PMID: 11788611 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
P67L: a cystic fibrosis allele with mild effects found at high frequency in the Scottish population. | Gilfillan A | Journal of medical genetics | 1998 | PMID: 9507391 |
Screening Young syndrome patients for CFTR mutations. | Friedman KJ | American journal of respiratory and critical care medicine | 1995 | PMID: 7551394 |
Analysis of the CFTR gene confirms the high genetic heterogeneity of the Spanish population: 43 mutations account for only 78% of CF chromosomes. | Chillón M | Human genetics | 1994 | PMID: 7513293 |
Detection of 98.5% of the mutations in 200 Belgian cystic fibrosis alleles by reverse dot-blot and sequencing of the complete coding region and exon/intron junctions of the CFTR gene. | Cuppens H | Genomics | 1993 | PMID: 7508414 |
A mutation in CFTR produces different phenotypes depending on chromosomal background. | Kiesewetter S | Nature genetics | 1993 | PMID: 7506096 |
Mutations and sequence variations detected in the cystic fibrosis transmembrane conductance regulator (CFTR) gene: a report from the Cystic Fibrosis Genetic Analysis Consortium. | Tsui LC | Human mutation | 1992 | PMID: 1284534 |
Three novel mutations in the cystic fibrosis gene detected by chemical cleavage: analysis of variant splicing and a nonsense mutation. | Jones CT | Human molecular genetics | 1992 | PMID: 1284466 |
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Text-mined citations for rs121909015 ...
HelpRecord last updated Jan 13, 2025
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.