VCV001451295.9 - ClinVar

NM_000204.5(CFI):c.772G>A (p.Ala258Thr)

Germline

Classification

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.

(5)

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/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000204.5(CFI):c.772G>A (p.Ala258Thr)

Variation ID: 1451295 Accession: VCV001451295.9

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 4q25 4: 109760523 (GRCh38) [ NCBI UCSC ] 4: 110681679 (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	Apr 2, 2021	Oct 8, 2024	Jan 9, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000204.5:c.772G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000195.3:p.Ala258Thr	missense
NM_000204.4:c.772G>A
NM_001318057.2:c.772G>A	NP_001304986.2:p.Ala258Thr	missense
NM_001331035.2:c.772G>A	NP_001317964.1:p.Ala258Thr	missense
NM_001375278.1:c.772G>A	NP_001362207.1:p.Ala258Thr	missense
NM_001375279.1:c.772G>A	NP_001362208.1:p.Ala258Thr	missense
NM_001375280.1:c.772G>A	NP_001362209.1:p.Ala258Thr	missense
NM_001375281.1:c.772G>A	NP_001362210.1:p.Ala258Thr	missense
NM_001375282.1:c.772G>A	NP_001362211.1:p.Ala258Thr	missense
NM_001375283.1:c.772G>A	NP_001362212.1:p.Ala258Thr	missense
NM_001375284.1:c.163G>A	NP_001362213.1:p.Ala55Thr	missense
NR_164671.1:n.800G>A		non-coding transcript variant
NR_164672.1:n.800G>A		non-coding transcript variant
NR_164673.1:n.800G>A		non-coding transcript variant
NC_000004.12:g.109760523C>T
NC_000004.11:g.110681679C>T
NG_007569.1:g.46463G>A
LRG_48:g.46463G>A

... more HGVS ... less HGVS

Protein change

A258T, A55T

Other names

p.Ala258Thr
IVS5DS G-A, -1

Canonical SPDI

NC_000004.12:109760522:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

effect on RNA splicing; Variation Ontology [ VariO:0362]

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00010

Trans-Omics for Precision Medicine (TOPMed) 0.00010

Exome Aggregation Consortium (ExAC) 0.00011

The Genome Aggregation Database (gnomAD) 0.00014

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00031

Links

OMIM: 217030.0002 dbSNP: rs199688124 VarSome

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
Gene	OMIM	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.
CFI		-	-	GRCh38 GRCh37	502	515

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.
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 9, 2024	RCV001993198.6
Factor I deficiency	Pathogenic (1)	no assertion criteria provided	Feb 15, 1996	RCV002074443.1
Age related macular degeneration 13 Atypical hemolytic-uremic syndrome with I factor anomaly Factor I deficiency	Likely pathogenic (1)	criteria provided, single submitter	Mar 31, 2022	RCV002507693.1
CFI-related disorder	Pathogenic (1)	no assertion criteria provided	Feb 13, 2024	RCV004542199.2

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.
Likely pathogenic (Mar 31, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Factor I deficiency Atypical hemolytic-uremic syndrome with I factor anomaly Age related macular degeneration 13 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002809313.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Jan 30, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV004226768.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Publications: PubMed (10) PubMed: 18374984‚ 22710145‚ 25788521‚ 26826462‚ 29888403‚ 32510551‚ 32853637‚ 32908800‚ 35619721‚ 8613545 Other databases https://www.complement-db.org/ho… https://www.complement-db.org/home.php Comment: PP4, PM3_strong, PVS1_strong Number of individuals with the variant: 1
Pathogenic (Jan 09, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002237176.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (7) PubMed: 8613545‚ 18374984‚ 22710145‚ 26826462‚ 29888403‚ 17576681‚ 9536098 Comment: This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 258 of the CFI protein (p.Ala258Thr). … (more) This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 258 of the CFI protein (p.Ala258Thr). RNA analysis indicates that this missense change induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs199688124, gnomAD 0.02%). This missense change has been observed in individual(s) with CFI-related conditions (PMID: 8613545, 18374984, 22710145, 26826462, 29888403). It has also been observed to segregate with disease in related individuals. This variant is also known as 801-A. ClinVar contains an entry for this variant (Variation ID: 1451295). 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 tolerated. 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 skipping of exon 5, but is expected to preserve the integrity of the reading-frame (PMID: 8613545, 18374984). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Feb 15, 1996)	no assertion criteria provided Method: literature only	COMPLEMENT FACTOR I DEFICIENCY Affected status: not provided Allele origin: germline	OMIM Accession: SCV000033143.2 First in ClinVar: Apr 04, 2013 Last updated: Apr 02, 2021	Publications: PubMed (2) PubMed: 849647‚ 8613545 Comment on evidence: In a patient with complement factor I deficiency (CFID; 610984) originally reported by Thompson and Lachmann (1977), Vyse et al. (1996) identified compound heterozygosity for … (more) In a patient with complement factor I deficiency (CFID; 610984) originally reported by Thompson and Lachmann (1977), Vyse et al. (1996) identified compound heterozygosity for 2 mutations in the CFI gene: an 801G-A transition in the last nucleotide of exon 5 and H400L (217030.0001). The 801G-A transition is part of the donor splice site consensus sequence of the fifth intron, which was deleted from the mRNA transcript as a result of the mutation. (less)
Pathogenic (Feb 13, 2024)	no assertion criteria provided Method: clinical testing	CFI-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004779220.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: The CFI c.772G>A variant is predicted to result in the amino acid substitution p.Ala258Thr. This variant was reported in individuals with complement factor I deficiency, … (more) The CFI c.772G>A variant is predicted to result in the amino acid substitution p.Ala258Thr. This variant was reported in individuals with complement factor I deficiency, aHUS, and age-related macular degeneration (see for example - Seddon et al. 2013. PubMed ID: 24036952; de Jong et al. 2020. PubMed ID: 32510551; Naesens et al. 2020. PubMed ID: 32853637; Java et al. 2020. PubMed ID: 32908800; Khan et al. 2021. PubMed ID: 34153144). This variant is the final nucleotide of the exon and functional studies found this variant causes exon skipping (Ponce-Castro et al. 2008. PubMed ID: 18374984). This variant is reported in 0.024% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. (less)

Comment:

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 258 of the CFI protein (p.Ala258Thr). RNA analysis indicates that this missense change induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs199688124, gnomAD 0.02%). This missense change has been observed in individual(s) with CFI-related conditions (PMID: 8613545, 18374984, 22710145, 26826462, 29888403). It has also been observed to segregate with disease in related individuals. This variant is also known as 801-A. ClinVar contains an entry for this variant (Variation ID: 1451295). 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 tolerated. 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 skipping of exon 5, but is expected to preserve the integrity of the reading-frame (PMID: 8613545, 18374984). For these reasons, this variant has been classified as Pathogenic.

Comment:

The CFI c.772G>A variant is predicted to result in the amino acid substitution p.Ala258Thr. This variant was reported in individuals with complement factor I deficiency, aHUS, and age-related macular degeneration (see for example - Seddon et al. 2013. PubMed ID: 24036952; de Jong et al. 2020. PubMed ID: 32510551; Naesens et al. 2020. PubMed ID: 32853637; Java et al. 2020. PubMed ID: 32908800; Khan et al. 2021. PubMed ID: 34153144). This variant is the final nucleotide of the exon and functional studies found this variant causes exon skipping (Ponce-Castro et al. 2008. PubMed ID: 18374984). This variant is reported in 0.024% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Complement Factor I Variants in Complement-Mediated Renal Diseases.	Zhang Y	Frontiers in immunology	2022	PMID: 35619721
Plasma C3d levels as a diagnostic marker for complete complement factor I deficiency.	Naesens L	The Journal of allergy and clinical immunology	2021	PMID: 32853637
Functional Analysis of Rare Genetic Variants in Complement Factor I (CFI) using a Serum-Based Assay in Advanced Age-related Macular Degeneration.	Java A	Translational vision science & technology	2020	PMID: 32908800
Effect of rare coding variants in the CFI gene on Factor I expression levels.	de Jong S	Human molecular genetics	2020	PMID: 32510551
Genotype-phenotype correlations of low-frequency variants in the complement system in renal disease and age-related macular degeneration.	Geerlings MJ	Clinical genetics	2018	PMID: 29888403
Genetic analysis and functional characterization of novel mutations in a series of patients with atypical hemolytic uremic syndrome.	Szarvas N	Molecular immunology	2016	PMID: 26826462
Rare genetic variants in the CFI gene are associated with advanced age-related macular degeneration and commonly result in reduced serum factor I levels.	Kavanagh D	Human molecular genetics	2015	PMID: 25788521
Complement factor I deficiency: a not so rare immune defect: characterization of new mutations and the first large gene deletion.	Alba-Domínguez M	Orphanet journal of rare diseases	2012	PMID: 22710145
Molecular characterization of Complement Factor I deficiency in two Spanish families.	Ponce-Castro IM	Molecular immunology	2008	PMID: 18374984
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
Statistical features of human exons and their flanking regions.	Zhang MQ	Human molecular genetics	1998	PMID: 9536098
The molecular basis of hereditary complement factor I deficiency.	Vyse TJ	The Journal of clinical investigation	1996	PMID: 8613545
A second case of human C3b inhibitor (KAF) deficiency.	Thompson RA	Clinical and experimental immunology	1977	PMID: 849647
https://www.complement-db.org/home.php	-	-	-	-
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Text-mined citations for rs199688124 ...

These 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 19, 2024

ClinVar Genomic variation as it relates to human health

NM_000204.5(CFI):c.772G>A (p.Ala258Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs199688124 ...