ClinVar Genomic variation as it relates to human health
NM_000492.4(CFTR):c.137C>T (p.Ala46Val)
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.137C>T (p.Ala46Val)
Variation ID: 593277 Accession: VCV000593277.26
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q31.2 7: 117504336 (GRCh38) [ NCBI UCSC ] 7: 117144390 (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 Dec 16, 2018 May 1, 2024 Dec 21, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000492.4:c.137C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000483.3:p.Ala46Val missense NC_000007.14:g.117504336C>T NC_000007.13:g.117144390C>T NG_016465.4:g.43553C>T LRG_663:g.43553C>T LRG_663t1:c.137C>T LRG_663p1:p.Ala46Val - Protein change
- A46V
- Other names
- p.Ala46Val
- Canonical SPDI
- NC_000007.14:117504335:C:T
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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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0.00020 (T)
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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), exomes 0.00003
Exome Aggregation Consortium (ExAC) 0.00004
The Genome Aggregation Database (gnomAD) 0.00009
Trans-Omics for Precision Medicine (TOPMed) 0.00012
1000 Genomes Project 0.00020
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023
1000 Genomes Project 30x 0.00031
- 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
Help
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 |
3821 | 5195 |
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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Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Mar 1, 2022 | RCV000728272.10 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 7, 2023 | RCV000780112.3 | |
Uncertain significance (6) |
criteria provided, multiple submitters, no conflicts
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Dec 21, 2023 | RCV000757789.15 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 22, 2021 | RCV001592932.2 |
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. |
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Uncertain significance
(Sep 04, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000855825.1
First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018 |
Number of individuals with the variant: 2
Sex: mixed
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Uncertain significance
(Oct 19, 2019)
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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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Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV001167244.1
First in ClinVar: Mar 08, 2020 Last updated: Mar 08, 2020 |
Comment:
CFTR c.137C>T has not been reported in the literature, to our knowledge. This CFTR variant (rs151020603) is rare (<0.1%) in a large population dataset1 (gnomAD: … (more)
CFTR c.137C>T has not been reported in the literature, to our knowledge. This CFTR variant (rs151020603) is rare (<0.1%) in a large population dataset1 (gnomAD: 12/282150 total alleles; 0.004%; no homozygotes). There are conflicting interpretations of the pathogenicity of this variant in ClinVar. Three submitters classified it as a variant of uncertain clinical significance and one as likely pathogenic. Two bioinformatic tools queried predict that this substitution would be damaging, and the alanine residue at this position is highly evolutionarily conserved across all species assessed. This variant is located within the same residue as p.Ala46Asp, a previously reported alternate pathogenic missense variant. We consider the clinical significance of c.137C>T uncertain at this time. (less)
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Uncertain significance
(Jul 22, 2021)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV001821979.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Sex: mixed
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Uncertain significance
(Jul 22, 2021)
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criteria provided, single submitter
Method: clinical testing
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Congenital bilateral aplasia of vas deferens from CFTR mutation
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV001821980.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Sex: mixed
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Uncertain significance
(Jun 11, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV002540881.1
First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022 |
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Uncertain significance
(Aug 08, 2022)
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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: SCV000944038.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 46 of the CFTR protein (p.Ala46Val). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 46 of the CFTR protein (p.Ala46Val). This variant is present in population databases (rs151020603, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with CFTR-related conditions. ClinVar contains an entry for this variant (Variation ID: 593277). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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
(Mar 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV003799399.2
First in ClinVar: Feb 13, 2023 Last updated: Mar 04, 2023 |
Comment:
The CFTR c.137C>T; p.Ala46Val variant (rs151020603), to our knowledge, is not reported in the medical literature but is reported in the SickKids CFTR database in … (more)
The CFTR c.137C>T; p.Ala46Val variant (rs151020603), to our knowledge, is not reported in the medical literature but is reported in the SickKids CFTR database in an individual with a positive newborn screen (see link). This variant is reported in ClinVar (Variation ID: 593277) and is found in the African population with an allele frequency of 0.05% (12/24960 alleles) in the Genome Aggregation Database. Additionally, another variant at this codon (c.137C>A, p.Ala46Asp) have been reported in individuals with cystic fibrosis and is considered pathogenic (Tzetis 1995, Van Goor 2014). The alanine at codon 46 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.468). However, given the lack of clinical and functional data, the significance of the p.Ala46Val variant is uncertain at this time. References: SickKids CFTR database: http://www.genet.sickkids.on.ca/cftr/Home.html Tzetis M et al. Identification of two novel mutations (296 + 1G-C and A46D) in exon 2 of the CFTR gene in Greek cystic fibrosis patients. Mol Cell Probes. 1995 Aug;9(4):283-5. PMID: 7477025. Van Goor F et al. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros. 2014 Jan;13(1):29-36.PMID: 23891399. (less)
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Uncertain significance
(Dec 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: yes
Allele origin:
unknown
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Mendelics
Accession: SCV000886163.3
First in ClinVar: Feb 18, 2019 Last updated: Dec 24, 2023 |
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Uncertain significance
(Dec 07, 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: SCV000917156.3
First in ClinVar: Jun 02, 2019 Last updated: Feb 04, 2024 |
Comment:
Variant summary: CFTR c.137C>T (p.Ala46Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: CFTR c.137C>T (p.Ala46Val) results in a non-conservative amino acid change in 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 3.2e-05 in 250758 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.137C>T has been reported in the literature as a non-informative genotype (second allele not specified) in at-least one individual reportedly affected with Cystic Fibrosis (example, daSilvaFilho_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 32819855). A different variant located at the same codon (c.137C>A, p.Ala46Asp) has been classified as pathogenic, however, current evidence is insufficient to determine the effect of p.Ala46Val on protein function. Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Sep 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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Ambry Genetics
Accession: SCV002700966.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.A46V variant (also known as c.137C>T), located in coding exon 2 of the CFTR gene, results from a C to T substitution at nucleotide … (more)
The p.A46V variant (also known as c.137C>T), located in coding exon 2 of the CFTR gene, results from a C to T substitution at nucleotide position 137. The alanine at codon 46 is replaced by valine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Cystic Fibrosis
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001464070.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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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Extensive CFTR sequencing through NGS in Brazilian individuals with cystic fibrosis: unravelling regional discrepancies in the country. | da Silva Filho LVRF | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2021 | PMID: 32819855 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CFTR | - | - | - | - |
Text-mined citations for rs151020603 ...
HelpRecord last updated Sep 29, 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.