ClinVar Genomic variation as it relates to human health
NM_000492.4(CFTR):c.4276T>C (p.Ser1426Pro)
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.
Pathogenic(1); Uncertain significance(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000492.4(CFTR):c.4276T>C (p.Ser1426Pro)
Variation ID: 53937 Accession: VCV000053937.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q31.2 7: 117666941 (GRCh38) [ NCBI UCSC ] 7: 117306995 (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 Mar 17, 2018 May 1, 2024 Nov 25, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000492.4:c.4276T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000483.3:p.Ser1426Pro missense NC_000007.14:g.117666941T>C NC_000007.13:g.117306995T>C NG_016465.4:g.206158T>C NG_056133.2:g.1347T>C LRG_663:g.206158T>C LRG_663t1:c.4276T>C LRG_663p1:p.Ser1426Pro - Protein change
- S1426P
- Other names
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- Canonical SPDI
- NC_000007.14:117666940:T: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.
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
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 |
3703 | 5024 | |
LOC111674477 | - | - | - | GRCh38 | - | 171 |
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
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
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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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Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Nov 25, 2023 | RCV000665842.15 | |
Pathogenic (2) |
criteria provided, single submitter
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Jan 29, 2018 | RCV001009481.10 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 15, 2023 | RCV003317064.8 |
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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Uncertain significance
(Jul 28, 2015)
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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: SCV002631586.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.S1426P variant (also known as c.4276T>C), located in coding exon 27 of the CFTR gene, results from a T to C substitution at nucleotide … (more)
The p.S1426P variant (also known as c.4276T>C), located in coding exon 27 of the CFTR gene, results from a T to C substitution at nucleotide position 4276. The serine at codon 1426 is replaced by proline, an amino acid with similar properties. This variant was reported in one patient with congenital absence of the vas deferens (CAVD) who was also heterozygous for deltaF508, however the phase was unknown (Steiner et al. Hum Mutat. 2011;32: 912). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be possibly damaging by PolyPhen but tolerated by SIFT in silico analyses. Since clinical data on this variant is limited at this time, its clinical significance is unclear. (less)
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Uncertain significance
(Mar 14, 2017)
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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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Counsyl
Accession: SCV000790028.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Pathogenic
(Jan 29, 2018)
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criteria provided, single submitter
Method: curation
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CFTR-related disorders
Affected status: yes
Allele origin:
germline
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CFTR-France
Accession: SCV001169576.1
First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020 |
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Uncertain significance
(Jun 15, 2023)
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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: SCV000697022.2
First in ClinVar: Mar 17, 2018 Last updated: Jul 29, 2023 |
Comment:
Variant summary: CFTR c.4276T>C (p.Ser1426Pro) results in a non-conservative amino acid change to a well-conserved residue (HGMD) located in the ABC transporter-like, ATP-binding domain (IPR003439) … (more)
Variant summary: CFTR c.4276T>C (p.Ser1426Pro) results in a non-conservative amino acid change to a well-conserved residue (HGMD) located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251444 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4276T>C has been found in one CBAVD patient published in the literature in a compound heterozygous state with deltaF508 (Steiner_Hum Mut_2011). The UMD database lists one reportedly unpublished CBAVD patient that also carried deltaF508 (phase unknown). It was also found in a heterozygous state without a second variant identified in an infant with respiratory distress (Tanriverdi_2021) and in one with acute pancreatitis (Abu-El-Haija_2019). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21520337, 25735457, 34996830, 36249513, 31088717, 31682332). Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Nov 25, 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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Invitae
Accession: SCV002132672.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 1426 of the CFTR protein (p.Ser1426Pro). … (more)
This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 1426 of the CFTR protein (p.Ser1426Pro). This variant is present in population databases (rs397508708, gnomAD 0.006%). This missense change has been observed in individual(s) with congenital bilateral absence of the vas deferens (CBAVD) and/or pancreatitis (PMID: 21520337, 31088717). ClinVar contains an entry for this variant (Variation ID: 53937). 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%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Jul 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: SCV002075967.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 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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Determination of Cystic Fibrosis Mutation Frequency in Preterm and Term Neonates with Respiratory Tract Problems. | Tanriverdi S | Balkan journal of medical genetics : BJMG | 2022 | PMID: 36249513 |
C FTR variants are associated with chronic bronchitis in smokers. | Saferali A | The European respiratory journal | 2022 | PMID: 34996830 |
Cystic fibrosis newborn screening in Denmark: Experience from the first 2 years. | Skov M | Pediatric pulmonology | 2020 | PMID: 31682332 |
Genetic variants in acute, acute recurrent and chronic pancreatitis affect the progression of disease in children. | Abu-El-Haija M | Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] | 2019 | PMID: 31088717 |
Comparative ex vivo, in vitro and in silico analyses of a CFTR splicing mutation: Importance of functional studies to establish disease liability of mutations. | Ramalho AS | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2016 | PMID: 25735457 |
Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. | Steiner B | Human mutation | 2011 | PMID: 21520337 |
Text-mined citations for rs397508708 ...
HelpRecord last updated May 08, 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.