Submissions for variant NM_000186.4(CFH):c.3628C>T (p.Arg1210Cys)

gnomAD frequency: 0.00019  dbSNP: rs121913059

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000022540	SCV000915378	pathogenic	Age related macular degeneration 4	2018-08-09	criteria provided, single submitter	clinical testing	Across a selection of the available literature, the CFH c.3628C>T (p.Arg1210Cys) missense variant has been identified in a heterozygous state in at least 70 patients with macular degeneration (Raychaundhuri et al. 2011; Zhan et al. 2013; Seddon et al. 2014; Duvvari et al. 2015). The p.Arg1210Cys variant was reported in a heterozygous state in two out of over 4,480 controls and is reported at a frequency of 0.00031 in the European (non-Finnish) population of the Genome Aggregation Database. Functional analysis of the p.Arg1210Cys variant using serum from a heterozygous individual as well as recombinant factor H protein suggests this variant reduces the binding of factor H to various ligands including heparin, endothelial cells, and Cb3 (Manuelian et al. 2003). Based on the collective evidence, the p.Arg1210Cys variant is classified as pathogenic for macular degeneration. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Illumina Laboratory Services, Illumina	RCV001099303	SCV001255748	uncertain significance	CFH-Related Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type II	2017-06-16	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001099304	SCV001255749	uncertain significance	Basal laminar drusen	2017-06-16	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV001508947	SCV001715390	pathogenic	not provided	2024-06-20	criteria provided, single submitter	clinical testing	PS3, PS4
Fulgent Genetics, Fulgent Genetics	RCV001536004	SCV001752680	pathogenic	Basal laminar drusen; Factor H deficiency; Hemolytic uremic syndrome, atypical, susceptibility to, 1; Age related macular degeneration 4	2021-06-30	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001508947	SCV002019217	pathogenic	not provided	2020-11-18	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002293983	SCV002587142	uncertain significance	Kidney disorder	2017-01-16	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004814908	SCV005071120	pathogenic	Retinal dystrophy	2023-01-01	criteria provided, single submitter	clinical testing
OMIM	RCV000018025	SCV000038304	pathogenic	Factor H deficiency	2015-07-01	no assertion criteria provided	literature only
OMIM	RCV000018026	SCV000038305	risk factor	Hemolytic uremic syndrome, atypical, susceptibility to, 1	2015-07-01	no assertion criteria provided	literature only
OMIM	RCV000022540	SCV000043829	risk factor	Age related macular degeneration 4	2015-07-01	no assertion criteria provided	literature only
Sydney Genome Diagnostics, Children's Hospital Westmead	RCV001328126	SCV001449218	pathogenic	Atypical hemolytic-uremic syndrome	2018-10-25	no assertion criteria provided	clinical testing	This patient is homozygous for a known pathogenic variant, c.3628C>T p.(Arg1210Cys), in the CFH gene. This variant, located in the C-terminal of complement factor H (CFH), has been shown in functional assays to reduce the binding of the central complement component C3b/C3d to heparin and endothelial cells (Manuelian et al 2003 J. Clin. Invest. 111:1181-90). Testing of the parental samples revealed both the father (see MG-15-2426) and mother (see MG-15-2425) are heterozygous for the c.3628C>T p.(Arg1210Cys) variant and confirms homozygosity for this variant in this patient.
GeneReviews	RCV000018026	SCV001981609	not provided	Hemolytic uremic syndrome, atypical, susceptibility to, 1		no assertion provided	literature only	Common pathogenic variant [Martinez-Barricarte et al 2008]