Submissions for variant NM_000186.4(CFH):c.1825G>A (p.Val609Ile)

gnomAD frequency: 0.00042  dbSNP: rs148165372

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001298731	SCV001487797	uncertain significance	not provided	2024-12-26	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 609 of the CFH protein (p.Val609Ile). This variant is present in population databases (rs148165372, gnomAD 0.05%). This missense change has been observed in individual(s) with clinical features of CFH-related conditions (PMID: 20513133, 34508573). ClinVar contains an entry for this variant (Variation ID: 988218). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change does not substantially affect CFH function (PMID: 34189567). 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.
Fulgent Genetics, Fulgent Genetics	RCV002486019	SCV002792094	uncertain significance	Basal laminar drusen; Factor H deficiency; Hemolytic uremic syndrome, atypical, susceptibility to, 1; Age related macular degeneration 4	2024-05-23	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003449825	SCV004180837	uncertain significance	Hemolytic uremic syndrome, atypical, susceptibility to, 1	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003449828	SCV004180838	uncertain significance	Age related macular degeneration 4	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003449827	SCV004180839	uncertain significance	Basal laminar drusen	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003449826	SCV004180840	uncertain significance	Factor H deficiency	2023-04-11	criteria provided, single submitter	clinical testing
Sydney Genome Diagnostics, Children's Hospital Westmead	RCV001328245	SCV001449223	uncertain significance	Atypical hemolytic-uremic syndrome	2018-12-17	no assertion criteria provided	clinical testing	This individual is heterozygous for the c.1825G>A variant in the CFH gene, which results in the amino acid substitution of valine to isoleucine at residue 609, p.Val609Ile. This variant has been reported in multiple individuals with aHUS and C3 glomerulopathy in the Database of complement gene variants (https://www.complement-db.org/home.php v3.0). This variant has also been reported in the gnomAD browser (http://gnomad.broadinstitute.org) with an allele frequency of 0.051% (65/126,312 alleles) in the European population. In silico analysis of pathogenicity (through Alamut Visual v2.8.1) using PolyPhen2, SIFT and MutationTaster suggest that this variant does not affect protein function and is likely to be benign. However, this analysis alone cannot be used to exclude pathogenicity. This variant is considered to be a variant of uncertain clinical significance (VOUS) according to the ACMG guidelines (evidence used: BP4).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001298731	SCV001553665	uncertain significance	not provided		no assertion criteria provided	clinical testing	The CFH p.Val609Ile variant was identified in 5 of 492 proband chromosomes (frequency: 0.01) from individuals with atypical haemolytic uraemic syndrome (Sheerin_2016 PMID:25899302; Bu_2014_PMID:24029428; Maga_2010_PMID:20513133; Feng_2013_PMID:23847193). The variant was also identified in a case study of a 62-year old woman with atypical haemolytic uraemic syndrome triggered by monoclonal gammopathy of renal significance; the variant was reported as a variant of uncertain significance (Mahmood_2017_PMID:28176474). The variant was identified in dbSNP (ID: rs148165372) but was not identified in ClinVar or LOVD 3.0. The variant was identified in control databases in 80 of 282404 chromosomes at a frequency of 0.0002833 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 66 of 128800 chromosomes (freq: 0.000512), African in 10 of 24964 chromosomes (freq: 0.000401), Other in 1 of 7208 chromosomes (freq: 0.000139) and European (Finnish) in 3 of 25118 chromosomes (freq: 0.000119), but was not observed in the Latino, Ashkenazi Jewish, East Asian, or South Asian populations. The p.Val609 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.