This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
ClinVar Genomic variation as it relates to human health
NM_000492.4(CFTR):c.1666A>G (p.Ile556Val)
Germline
Classification
Help
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.
(15)
Help
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.
Conflicting classifications of pathogenicity
Pathogenic(1); Uncertain significance(1); Benign(4); Likely benign(5)
Pathogenic(1); Uncertain significance(1); Benign(4); Likely benign(5)
15
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000492.4(CFTR):c.1666A>G (p.Ile556Val)
Variation ID: 7196 Accession: VCV000007196.49
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 7q31.2 7: 117587820 (GRCh38) [ NCBI UCSC ] 7: 117227874 (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 Jun 28, 2015 May 1, 2024 Feb 1, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000492.4:c.1666A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000483.3:p.Ile556Val missense NC_000007.14:g.117587820A>G NC_000007.13:g.117227874A>G NG_016465.4:g.127037A>G NG_056131.3:g.775A>G LRG_663:g.127037A>G LRG_663t1:c.1666A>G LRG_663p1:p.Ile556Val - Protein change
- I556V
- Other names
- -
- Canonical SPDI
- NC_000007.14:117587819:A:G
-
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.
-
0.01118 (G)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00119
Trans-Omics for Precision Medicine (TOPMed) 0.00213
Exome Aggregation Consortium (ExAC) 0.00291
The Genome Aggregation Database (gnomAD), exomes 0.00351
1000 Genomes Project 30x 0.00968
1000 Genomes Project 0.01118
- 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 |
3832 | 5210 | |
| LOC111674475 | - | - | - | GRCh38 | - | 145 |
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. |
|---|---|---|---|---|
| Benign/Likely benign (8) |
criteria provided, multiple submitters, no conflicts
|
Feb 1, 2024 | RCV000007617.35 | |
| Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Apr 17, 2023 | RCV000046398.26 | |
| Benign (1) |
criteria provided, single submitter
|
Oct 17, 2014 | RCV000174251.15 | |
| Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Jan 24, 2024 | RCV001009505.18 |
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. |
|
|---|---|---|---|---|---|
|
Benign
(Oct 17, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000225525.5
First in ClinVar: Jun 28, 2015 Last updated: May 03, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
|
Likely benign
(Dec 13, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001134120.3
First in ClinVar: Jan 05, 2020 Last updated: Jan 26, 2021 |
|
|
|
Likely benign
(Jul 22, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV001822067.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Sex: mixed
|
|
|
Benign
(Feb 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000074411.12
First in ClinVar: Jul 03, 2013 Last updated: Feb 14, 2024 |
|
|
|
Likely benign
(May 23, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000791753.1
First in ClinVar: Aug 04, 2018 Last updated: Aug 04, 2018 |
|
|
|
Likely benign
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
CFTR-Related Disorders
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000466517.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
|
|
|
Benign
(Sep 07, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: unknown
Allele origin:
germline
|
Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV001905497.1
First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
|
|
|
Uncertain significance
(Feb 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV002540895.3
First in ClinVar: Jul 09, 2022 Last updated: Jan 26, 2024 |
Comment:
BS1, BS2
Number of individuals with the variant: 3
|
|
|
Pathogenic
(Jan 24, 2024)
|
criteria provided, single submitter
Method: curation
|
CFTR-related disorders
Affected status: no, yes
Allele origin:
germline
|
CFTR-France
Accession: SCV001169600.2
First in ClinVar: Mar 16, 2020 Last updated: Feb 14, 2024 |
Observation 1:
Number of individuals with the variant: 1
Sex: male
Observation 2:
Number of individuals with the variant: 1
Sex: male
Observation 3:
Number of individuals with the variant: 1
Sex: female
|
|
|
Likely benign
(Apr 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000602989.7
First in ClinVar: Jun 28, 2015 Last updated: Feb 20, 2024 |
|
|
|
Benign
(Dec 08, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV001173099.5
First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024 |
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more)
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
|
|
|
Benign
(Mar 23, 2018)
|
no assertion criteria provided
Method: clinical testing
|
CFTR-related disorders
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002080639.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
|
|
Benign
(Aug 14, 2015)
|
no assertion criteria provided
Method: clinical testing
|
Cystic Fibrosis
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000052133.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 11, 2015 |
|
|
|
Uncertain significance
(May 15, 1994)
|
Flagged submission
flagged submission
Method: literature only
Reason: Older claim that does not account for recent evidence
Source: ClinGen
|
RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000027818.3
First in ClinVar: Apr 04, 2013 Last updated: May 14, 2018 |
Comment on evidence:
This variant, formerly titled CYSTIC FIBROSIS, has been reclassified based on a review of the gnomAD database by Hamosh (2018). In a study of 224 … (more)
This variant, formerly titled CYSTIC FIBROSIS, has been reclassified based on a review of the gnomAD database by Hamosh (2018). In a study of 224 non-F508del cystic fibrosis (CF; 219700) chromosomes, Ghanem et al. (1994) identified a C-to-T substitution at nucleotide 223, changing arginine to cysteine at position 31, in a French couple with cystic fibrosis and one affected child. Since their apparently unaffected 6-year-old child was found to be homozygous for this mutation, it is probably a polymorphism. The father and the affected child had another substitution changing an isoleucine-556 to valine in exon 11. This mutation can be detected by restriction analysis since it abolishes a HhaI recognition sequence. Hamosh (2018) found that the I556V variant was present in heterozygous state in 914 of 276,478 alleles and in 28 homozygotes in the gnomAD database, with an allelic frequency of 0.0033 (May 3, 2018). (less)
|
|
|
Uncertain significance
(Sep 05, 2022)
|
Flagged submission
flagged submission
Method: curation
Reason: Clinical significance appears to be a case-level interpretation inconsistent with variant classification
Source: ClinGen
|
Cystic fibrosis
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV002573992.1
First in ClinVar: Sep 24, 2022 Last updated: Sep 24, 2022 |
Comment:
This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project … (more)
This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PM3, BS1, BS2 (less)
Number of individuals with the variant: 1
|
|
| click to load more click to collapse | |||||
| Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more | |||||
Comment:
Comment:
BS1, BS2
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Comment:
This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PM3, BS1, BS2
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:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Comment:
BS1, BS2
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Comment:
This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PM3, BS1, BS2
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Next-generation sequencing for identifying genetic mutations in adults with bronchiectasis. | Guan WJ | Journal of thoracic disease | 2018 | PMID: 29997923 |
| Pathogenic role of ADGRG2 in CBAVD patients replicated in Chinese population. | Yang B | Andrology | 2017 | PMID: 28805948 |
| 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 |
| NGS-Based Assay for the Identification of Individuals Carrying Recessive Genetic Mutations in Reproductive Medicine. | Abulí A | Human mutation | 2016 | PMID: 26990548 |
| Clinical Phenotypes and Genotypic Spectrum of Cystic Fibrosis in Chinese Children. | Shen Y | The Journal of pediatrics | 2016 | PMID: 26826884 |
| The Spectrum of CFTR Variants in Nonwhite Cystic Fibrosis Patients: Implications for Molecular Diagnostic Testing. | Schrijver I | The Journal of molecular diagnostics : JMD | 2016 | PMID: 26708955 |
| Utility of whole-genome sequencing for detection of newborn screening disorders in a population cohort of 1,696 neonates. | Bodian DL | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26334177 |
| Functional characteristics of L1156F-CFTR associated with alcoholic chronic pancreatitis in Japanese. | Kondo S | American journal of physiology. Gastrointestinal and liver physiology | 2015 | PMID: 26089335 |
| Cystic fibrosis transmembrane conductance regulator gene variants are associated with autoimmune pancreatitis and slow response to steroid treatment. | Chang MC | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2015 | PMID: 25869325 |
| Characterization of gene mutations and phenotypes of cystic fibrosis in Chinese patients. | Liu Y | Respirology (Carlton, Vic.) | 2015 | PMID: 25580864 |
| Different cystic fibrosis transmembrane conductance regulator mutations in Chinese men with congenital bilateral absence of vas deferens and other acquired obstructive azoospermia. | Lu S | Urology | 2013 | PMID: 23953609 |
| Novel CFTR variants identified during the first 3 years of cystic fibrosis newborn screening in California. | Prach L | The Journal of molecular diagnostics : JMD | 2013 | PMID: 23810505 |
| Carrier testing for severe childhood recessive diseases by next-generation sequencing. | Bell CJ | Science translational medicine | 2011 | PMID: 21228398 |
| A map of human genome variation from population-scale sequencing. | 1000 Genomes Project Consortium | Nature | 2010 | PMID: 20981092 |
| Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation associated with a congenital bilateral absence of vas deferens. | Sakamoto H | International journal of urology : official journal of the Japanese Urological Association | 2008 | PMID: 18304229 |
| Association of cystic fibrosis transmembrane conductance regulator (CFTR) mutation/variant/haplotype and tumor necrosis factor (TNF) promoter polymorphism in hyperlipidemic pancreatitis. | Chang YT | Clinical chemistry | 2008 | PMID: 17981921 |
| Spectrum of mutations and variants/haplotypes of CFTR and genotype-phenotype correlation in idiopathic chronic pancreatitis and controls in Chinese by complete analysis. | Chang MC | Clinical genetics | 2007 | PMID: 17539902 |
| Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in Asians with chronic pulmonary disease: a pilot study. | Ngiam NS | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2006 | PMID: 16678503 |
| A haplotype-based molecular analysis of CFTR mutations associated with respiratory and pancreatic diseases. | Lee JH | Human molecular genetics | 2003 | PMID: 12952861 |
| Variant cystic fibrosis phenotypes in the absence of CFTR mutations. | Groman JD | The New England journal of medicine | 2002 | PMID: 12167682 |
| CFTR gene mutations in adults with disseminated bronchiectasis. | Girodon E | European journal of human genetics : EJHG | 1997 | PMID: 9272738 |
| Identification of eight mutations and three sequence variations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. | Ghanem N | Genomics | 1994 | PMID: 7522211 |
| Cystic fibrosis patients bearing both the common missense mutation Gly----Asp at codon 551 and the delta F508 mutation are clinically indistinguishable from delta F508 homozygotes, except for decreased risk of meconium ileus. | Hamosh A | American journal of human genetics | 1992 | PMID: 1379413 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CFTR | - | - | - | - |
| http://www.genet.sickkids.on.ca/app | - | - | - | - |
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Text-mined citations for rs75789129 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 25, 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.