NM_000204.5(CFI):c.1642G>C (p.Glu548Gln) AND not specified

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jul 3, 2024
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001821053.5

Allele description [Variation Report for NM_000204.5(CFI):c.1642G>C (p.Glu548Gln)]

NM_000204.5(CFI):c.1642G>C (p.Glu548Gln)

Gene:

CFI:complement factor I [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

4q25

Genomic location:

Preferred name:

NM_000204.5(CFI):c.1642G>C (p.Glu548Gln)

HGVS:

NC_000004.12:g.109741003C>G
NG_007569.1:g.65983G>C
NM_000204.5:c.1642G>CMANE SELECT
NM_001318057.2:c.1666G>C
NM_001331035.2:c.1621G>C
NM_001375278.1:c.1558+1488G>C
NM_001375279.1:c.1534+1488G>C
NM_001375280.1:c.1513+1488G>C
NM_001375281.1:c.1534+1488G>C
NM_001375282.1:c.1513+1488G>C
NM_001375283.1:c.1585G>C
NM_001375284.1:c.1033G>C
NP_000195.2:p.Glu548Gln
NP_000195.3:p.Glu548Gln
NP_001304986.2:p.Glu556Gln
NP_001317964.1:p.Glu541Gln
NP_001362212.1:p.Glu529Gln
NP_001362213.1:p.Glu345Gln
LRG_48t1:c.1642G>C
LRG_48:g.65983G>C
NC_000004.11:g.110662159C>G
NM_000204.3:c.1642G>C
NM_000204.4:c.1642G>C
NR_164671.1:n.1389G>C
NR_164672.1:n.1692G>C
NR_164673.1:n.1666G>C
p.Glu548Gln

Protein change:

E345Q

Links:

dbSNP: rs7437875

NCBI 1000 Genomes Browser:

rs7437875

Molecular consequence:

NM_001375278.1:c.1558+1488G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001375279.1:c.1534+1488G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001375280.1:c.1513+1488G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001375281.1:c.1534+1488G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001375282.1:c.1513+1488G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000204.5:c.1642G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001318057.2:c.1666G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001331035.2:c.1621G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001375283.1:c.1585G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001375284.1:c.1033G>C - missense variant - [Sequence Ontology: SO:0001583]
NR_164671.1:n.1389G>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_164672.1:n.1692G>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_164673.1:n.1666G>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002066468	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 4, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005203707	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Jul 3, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 27268256, 37369098 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002066468

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jan 4, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV005203707

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely benign
(Jul 3, 2024)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Chromosomal rearrangement-A rare cause of complement factor I associated atypical haemolytic uraemic syndrome.

Gleeson PJ, Wilson V, Cox TE, Sharma SD, Smith-Jackson K, Strain L, Lappin D, McHale T, Kavanagh D, Goodship TH.

Immunobiology. 2016 Oct;221(10):1124-30. doi: 10.1016/j.imbio.2016.05.002. Epub 2016 May 10.

PubMed [citation]

PMID:: 27268256

See all PubMed Citations (3)

Details of each submission

From Genetic Services Laboratory, University of Chicago, SCV002066468.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

DNA sequence analysis of the CFI gene demonstrated a sequence change, c.1642G>C, in exon 13 that results in an amino acid change, p.Glu548Gln. This sequence change has been described in the gnomAD database with a relatively high frequency of 0.52% in the African sub-population (dbSNP rs7437875). The p.Glu548Gln change has been reported in an individual with atypical hemolytic uremic syndrome (PMID: 27268256) and an individual with thrombotic thrombocytopenic pupura; however, this individual was also compound heterozygous for two variants in the ADAMTS13 gene (PMID: 30046676). Additionally, a different amino acid change at the same location (p.Glu548Gly) has been reported in association with atypical hemolytic uremic syndrome (PMID: 27268256). The p.Glu548Gln change affects a moderately conserved amino acid residue located in a domain of the CFI protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Glu548Gln substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Glu548Gln change remains unknown at this time.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005203707.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: CFI c.1642G>C (p.Glu548Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00071 in 251290 control chromosomes, predominantly at a frequency of 0.005 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 50000 fold of the estimated maximal expected allele frequency for a pathogenic variant in CFI causing Genetic Atypical Hemolytic Uremic Syndrome phenotype (1e-07). c.1642G>C has been reported in the literature in individuals affected with Genetic Atypical Hemolytic Uremic Syndrome without evidence of causality (e.g. Gleeson_2016, Brocklebank_2023). These reports do not provide unequivocal conclusions about association of the variant with Genetic Atypical Hemolytic Uremic Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27268256, 37369098). ClinVar contains an entry for this variant (Variation ID: 347147). Based on the evidence outlined above, the variant was classified as likely benign.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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