ClinVar Genomic variation as it relates to human health
NM_000204.5(CFI):c.148C>G (p.Pro50Ala)
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_000204.5(CFI):c.148C>G (p.Pro50Ala)
Variation ID: 899590 Accession: VCV000899590.7
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4q25 4: 109766734 (GRCh38) [ NCBI UCSC ] 4: 110687890 (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 May 31, 2020 Feb 14, 2024 Dec 10, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000204.5:c.148C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000195.3:p.Pro50Ala missense NM_001318057.2:c.148C>G NP_001304986.2:p.Pro50Ala missense NM_001331035.2:c.148C>G NP_001317964.1:p.Pro50Ala missense NM_001375278.1:c.148C>G NP_001362207.1:p.Pro50Ala missense NM_001375279.1:c.148C>G NP_001362208.1:p.Pro50Ala missense NM_001375280.1:c.148C>G NP_001362209.1:p.Pro50Ala missense NM_001375281.1:c.148C>G NP_001362210.1:p.Pro50Ala missense NM_001375282.1:c.148C>G NP_001362211.1:p.Pro50Ala missense NM_001375283.1:c.148C>G NP_001362212.1:p.Pro50Ala missense NM_001375284.1:c.-127-5042C>G intron variant NR_164671.1:n.176C>G non-coding transcript variant NR_164672.1:n.176C>G non-coding transcript variant NR_164673.1:n.176C>G non-coding transcript variant NC_000004.12:g.109766734G>C NC_000004.11:g.110687890G>C NG_007569.1:g.40252C>G LRG_48:g.40252C>G LRG_48t1:c.148C>G - Protein change
- P50A
- Other names
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- Canonical SPDI
- NC_000004.12:109766733: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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0.00020 (C)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00006
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00009
The Genome Aggregation Database (gnomAD), exomes 0.00010
Exome Aggregation Consortium (ExAC) 0.00011
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
- 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
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. |
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CFI | - | - |
GRCh38 GRCh37 |
491 | 503 |
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
Help
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 (1) |
criteria provided, single submitter
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Apr 28, 2017 | RCV001144251.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 10, 2023 | RCV001858947.3 |
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
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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
(Apr 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Atypical hemolytic-uremic syndrome with I factor anomaly
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001304840.1
First in ClinVar: May 31, 2020 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Dec 10, 2023)
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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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Invitae
Accession: SCV002139195.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 50 of the CFI protein (p.Pro50Ala). … (more)
This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 50 of the CFI protein (p.Pro50Ala). This variant is present in population databases (rs144082872, gnomAD 0.03%). This missense change has been observed in individual(s) with atypical hemolytic uremic syndrome and age-related macular degeneration (PMID: 20016463, 24034049, 24036952, 31249236). ClinVar contains an entry for this variant (Variation ID: 899590). 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 CFI protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CFI function (PMID: 35069568). 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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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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Functional Analysis of Variants in Complement Factor I Identified in Age-Related Macular Degeneration and Atypical Hemolytic Uremic Syndrome. | de Jong S | Frontiers in immunology | 2022 | PMID: 35069568 |
Does severe ADAMTS13 deficiency in thrombotic microangiopathy rule out complement-mediated atypical hemolytic uremic syndrome. | Arumugam V | Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia | 2019 | PMID: 31249236 |
Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration. | Seddon JM | Nature genetics | 2013 | PMID: 24036952 |
A newly identified mutation in the complement factor I gene not associated with early post-transplant recurrence of atypical hemolytic-uremic syndrome: a case report. | Ranghino A | Transplantation proceedings | 2013 | PMID: 24034049 |
The role of complement in Streptococcus pneumoniae-associated haemolytic uraemic syndrome. | Szilágyi A | Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association | 2013 | PMID: 23787556 |
Combined complement gene mutations in atypical hemolytic uremic syndrome influence clinical phenotype. | Bresin E | Journal of the American Society of Nephrology : JASN | 2013 | PMID: 23431077 |
Mutations in components of complement influence the outcome of Factor I-associated atypical hemolytic uremic syndrome. | Bienaime F | Kidney international | 2010 | PMID: 20016463 |
Mutations in complement factor I as found in atypical hemolytic uremic syndrome lead to either altered secretion or altered function of factor I. | Nilsson SC | European journal of immunology | 2010 | PMID: 19877009 |
Text-mined citations for rs144082872 ...
HelpRecord last updated Feb 20, 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.