VCV000372807.7 - ClinVar

NM_000204.5(CFI):c.452A>G (p.Asn151Ser)

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.

(3)

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
Likely pathogenic(1); Uncertain significance(2)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000204.5(CFI):c.452A>G (p.Asn151Ser)

Variation ID: 372807 Accession: VCV000372807.7

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 4q25 4: 109764567 (GRCh38) [ NCBI UCSC ] 4: 110685723 (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	Jan 9, 2017	Feb 14, 2024	Jun 4, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000204.5:c.452A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000195.3:p.Asn151Ser	missense
NM_000204.4:c.452A>G
NM_001318057.2:c.452A>G	NP_001304986.2:p.Asn151Ser	missense
NM_001331035.2:c.452A>G	NP_001317964.1:p.Asn151Ser	missense
NM_001375278.1:c.452A>G	NP_001362207.1:p.Asn151Ser	missense
NM_001375279.1:c.452A>G	NP_001362208.1:p.Asn151Ser	missense
NM_001375280.1:c.452A>G	NP_001362209.1:p.Asn151Ser	missense
NM_001375281.1:c.452A>G	NP_001362210.1:p.Asn151Ser	missense
NM_001375282.1:c.452A>G	NP_001362211.1:p.Asn151Ser	missense
NM_001375283.1:c.452A>G	NP_001362212.1:p.Asn151Ser	missense
NM_001375284.1:c.-127-2875A>G		intron variant
NR_164671.1:n.480A>G		non-coding transcript variant
NR_164672.1:n.480A>G		non-coding transcript variant
NR_164673.1:n.480A>G		non-coding transcript variant
NC_000004.12:g.109764567T>C
NC_000004.11:g.110685723T>C
NG_007569.1:g.42419A>G
LRG_48:g.42419A>G
LRG_48t1:c.452A>G

... more HGVS ... less HGVS

Protein change

N151S

Other names

Canonical SPDI

NC_000004.12:109764566:T:C

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

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.

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00003

Trans-Omics for Precision Medicine (TOPMed) 0.00003

Links

ClinGen: CA3042272 dbSNP: rs772044176 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	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Jun 4, 2023	RCV000413659.7
Factor I deficiency	Uncertain significance (1)	criteria provided, single submitter	Apr 8, 2022	RCV003144247.3

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 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 (Aug 04, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000491335.1 First in ClinVar: Jan 09, 2017 Last updated: Jan 09, 2017	Comment: Published functional studies demonstrate that the N151S variant protein is expressed at reduced levels and shows a dramatic reduction in secretion, and is sensitive to … (more) Published functional studies demonstrate that the N151S variant protein is expressed at reduced levels and shows a dramatic reduction in secretion, and is sensitive to EndoH digestion indicating the protein is retained in the endoplasmic reticulum (Nilsson et al., 2010; Beinaime et al., 2010); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 17914026, 28187980, 30046676, 19877009, 23431077, 20016463, 26541438, 24161037, 28282489, 29566171, 29888403, 28911789, 30890598) (less)
Uncertain significance (Apr 08, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Factor I deficiency Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003831624.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Uncertain significance (Jun 04, 2023)	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: SCV002129027.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (8) PubMed: 19877009‚ 20016463‚ 17914026‚ 23431077‚ 28187980‚ 28282489‚ 29566171‚ 30046676 Comment: 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) … (more) 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. 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. Experimental studies have shown that this missense change affects CFI function (PMID: 19877009, 20016463). ClinVar contains an entry for this variant (Variation ID: 372807). This variant is also known as N133S. This missense change has been observed in individual(s) with atypical hemolytic uremia syndrome, age-related macular degeneration, C3 glomerulopathy, or hypertension-associated thrombotic microangiopathy (PMID: 17914026, 20016463, 23431077, 28187980, 28282489, 29566171, 30046676). This variant is present in population databases (rs772044176, gnomAD 0.009%). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 151 of the CFI protein (p.Asn151Ser). (less)

Comment:

Published functional studies demonstrate that the N151S variant protein is expressed at reduced levels and shows a dramatic reduction in secretion, and is sensitive to EndoH digestion indicating the protein is retained in the endoplasmic reticulum (Nilsson et al., 2010; Beinaime et al., 2010); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 17914026, 28187980, 30046676, 19877009, 23431077, 20016463, 26541438, 24161037, 28282489, 29566171, 29888403, 28911789, 30890598)

Comment:

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. 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. Experimental studies have shown that this missense change affects CFI function (PMID: 19877009, 20016463). ClinVar contains an entry for this variant (Variation ID: 372807). This variant is also known as N133S. This missense change has been observed in individual(s) with atypical hemolytic uremia syndrome, age-related macular degeneration, C3 glomerulopathy, or hypertension-associated thrombotic microangiopathy (PMID: 17914026, 20016463, 23431077, 28187980, 28282489, 29566171, 30046676). This variant is present in population databases (rs772044176, gnomAD 0.009%). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 151 of the CFI protein (p.Asn151Ser).

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
Genetic analysis of the complement pathway in C3 glomerulopathy.	Zhao W	Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association	2018	PMID: 29566171
Combined study of ADAMTS13 and complement genes in the diagnosis of thrombotic microangiopathies using next-generation sequencing.	Fidalgo T	Research and practice in thrombosis and haemostasis	2017	PMID: 30046676
Systematic Functional Testing of Rare Variants: Contributions of CFI to Age-Related Macular Degeneration.	Tan PL	Investigative ophthalmology & visual science	2017	PMID: 28282489
Patients with hypertension-associated thrombotic microangiopathy may present with complement abnormalities.	Timmermans SAMEG	Kidney international	2017	PMID: 28187980
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
Membrane cofactor protein mutations in atypical hemolytic uremic syndrome (aHUS), fatal Stx-HUS, C3 glomerulonephritis, and the HELLP syndrome.	Fang CJ	Blood	2008	PMID: 17914026

Text-mined citations for rs772044176 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000204.5(CFI):c.452A>G (p.Asn151Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs772044176 ...