Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_000186.4(CFH):c.565G>A(p.Glu189Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,612,400 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
CFH (HGNC:4883): (complement factor H) This gene is a member of the Regulator of Complement Activation (RCA) gene cluster and encodes a protein with twenty short consensus repeat (SCR) domains. This protein is secreted into the bloodstream and has an essential role in the regulation of complement activation, restricting this innate defense mechanism to microbial infections. Mutations in this gene have been associated with hemolytic-uremic syndrome (HUS) and chronic hypocomplementemic nephropathy. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Oct 2011]
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PM2
?
PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
BP4
?
BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (MetaRNN=0.19203624).
Factor H deficiency;C0730295:Basal laminar drusen;C1853147:Age related macular degeneration 4;C2749604:Hemolytic uremic syndrome, atypical, susceptibility to, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Fulgent Genetics, Fulgent Genetics
Apr 06, 2022
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Factor H deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Genome-Nilou Lab
Apr 11, 2023
- -
Hemolytic uremic syndrome, atypical, susceptibility to, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Genome-Nilou Lab
Apr 11, 2023
- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Invitae
May 01, 2023
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. 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 1355349). This variant has not been reported in the literature in individuals affected with CFH-related conditions. This variant is present in population databases (rs121913054, gnomAD 0.03%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 189 of the CFH protein (p.Glu189Lys). -
Basal laminar drusen Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Genome-Nilou Lab
Apr 11, 2023
- -
Age related macular degeneration 4 Uncertain:1
Uncertain significance, criteria provided, single submitter