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NC_000001.10:g.(196722206_?)_(?_196808505)del AND Age-related macular degeneration

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Feb 1, 2008
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
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:
RCV000030867.1

Allele description [Variation Report for NC_000001.10:g.(196722206_?)_(?_196808505)del]

NC_000001.10:g.(196722206_?)_(?_196808505)del

Genes:
CFHR1:complement factor H related 1 [Gene - OMIM - HGNC]
CFHR3:complement factor H related 3 [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
1q31.3
Genomic location:
Preferred name:
NC_000001.10:g.(196722206_?)_(?_196808505)del
HGVS:
  • NC_000001.11:g.(196753076_?)_(?_196839375)del
  • NC_000001.10:g.(196722206_?)_(?_196808505)del
Note:
84-kb deletion spanning CFHR1 and CFHR3 genes plus flanking genomic DNA.
Nucleotide change:
84-KB DEL
Links:
OMIM: 134371.0001; OMIM: 605336.0001

Condition(s)

Name:
Age-related macular degeneration (ARMD)
Synonyms:
MACULAR DEGENERATION, AGE-RELATED, REDUCED RISK OF
Identifiers:
MONDO: MONDO:0005150; MedGen: C0242383; OMIM: PS603075

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000025548OMIM
no assertion criteria provided
Pathogenic
(Feb 1, 2008)
germlineliterature only

PubMed (4)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only

Citations

PubMed

A common CFH haplotype, with deletion of CFHR1 and CFHR3, is associated with lower risk of age-related macular degeneration.

Hughes AE, Orr N, Esfandiary H, Diaz-Torres M, Goodship T, Chakravarthy U.

Nat Genet. 2006 Oct;38(10):1173-7. Epub 2006 Sep 24. Erratum in: Nat Genet. 2007 Apr;39(4):567.

PubMed [citation]
PMID:
16998489

Deletion of complement factor H-related genes CFHR1 and CFHR3 is associated with atypical hemolytic uremic syndrome.

Zipfel PF, Edey M, Heinen S, Józsi M, Richter H, Misselwitz J, Hoppe B, Routledge D, Strain L, Hughes AE, Goodship JA, Licht C, Goodship TH, Skerka C.

PLoS Genet. 2007 Mar 16;3(3):e41. Epub 2007 Feb 1.

PubMed [citation]
PMID:
17367211
PMCID:
PMC1828695
See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000025548.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (4)

Description

Hughes et al. (2006) identified an 84-kb deletion that occurred between 2 virtually identical 29-kb segments of duplication and was located downstream of the CFH gene and upstream of the CFHR4 gene. By sequence analysis in 3 individuals who were homozygous for the deletion, Zipfel et al. (2007) showed that the deletion resulted from nonallelic homologous recombination.

Hughes et al. (2006) found that a haplotype carrying a deletion of the CFHR1 and CFHR3 (605336) genes was associated with decreased risk of age-related macular degeneration (ARMD; see 603075), being present on 20% of chromosomes of controls and 8% of chromosomes of individuals with ARMD. The proteins encoded by these genes were absent in serum of homozygotes. The protective effect of the deletion haplotype could not be attributed to linkage disequilibrium with the Y402H variant of complement factor H (134370.0008) and was replicated in an independent sample.

Extending their previous work (see Hughes et al., 2006), Zipfel et al. (2007) found that the CFHR1/CFHR3 deletion was associated with an increased risk of atypical hemolytic-uremic syndrome (aHUS; 235400) in 2 independent European cohorts. In the first group, 19 (16%) of 121 aHUS patients had the deletion compared to 2 of 100 control individuals. Three of the patients had a homozygous deletion. All patients had normal serum factor H levels. In the second group comprising 66 patients, 28% had the deletion compared to 6% of controls. Ten percent and 2% of patients and controls, respectively, were homozygous for the deletion. In vitro functional expression studies showed that CFHR1/CFHR3-deficient plasma had decreased protective activity against erythrocyte lysis, suggesting a defective regulation of complement activation. Zipfel et al. (2007) noted that the present study showed an opposite effect for the variant from that of Hughes et al. (2006), which may be due to a disease-modifying action of the deletion or linkage disequilibrium between the deletion and other susceptibility alleles. Of 147 patients with aHUS, 121 of whom had previously been reported by Zipfel et al. (2007), Jozsi et al. (2008) identified serum anti-CFH autoantibodies in 16 (11%); 14 lacked CFHR1/CFHR3 completely and 2 showed extremely low CFHR1/CFHR3 plasma levels. The findings illustrated a new combination of 2 susceptibility factors for the development of aHUS.

The CFHR1/CFHR3 deletion exclusively occurs on one of the 2 protective CFH haplotypes, both of which are tagged by the protective allele of single-nucleotide polymorphism rs2274700 (A473A). In a German cohort of 530 ARMD patients, Fritsche et al. (2010) showed that protection against ARMD conferred by delta-CFHR3/CFHR1 was independent of the effects of CFH polymorphisms rs2274700 and rs1061170 (Y402H; 134370.0008). This suggested a functional role of CFHR1 and/or CFHR3 in disease pathogenesis. Fritsche et al. (2010) determined that CFHR3 is a novel human complement regulator that inhibits C3 (120700) convertase activity. CFHR3 displayed antiinflammatory effects by blocking C5A (see 120900) generation and C5A-mediated chemoattraction of neutrophils. In addition, CFHR3 and CFHR1 competed with factor H for binding to the central complement component C3. Thus, deficiency of CFHR3 and CFHR1 resulted in a loss of complement control but enhanced local regulation by factor H. Fritsche et al. (2010) hypothesized that dysregulation of complement may play a central role in ARMD pathology.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jan 26, 2024