Submissions for variant NM_000186.4(CFH):c.647T>C (p.Ile216Thr)

gnomAD frequency: 0.00003  dbSNP: rs183474263

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001308868	SCV001498343	uncertain significance	not provided	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 216 of the CFH protein (p.Ile216Thr). This variant is present in population databases (rs183474263, gnomAD 0.1%). This missense change has been observed in individual(s) with clinical features of CFH-related conditions (PMID: 22669321, 25814826). ClinVar contains an entry for this variant (Variation ID: 1011109). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The threonine 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	RCV002476425	SCV002775534	uncertain significance	Basal laminar drusen; Factor H deficiency; Hemolytic uremic syndrome, atypical, susceptibility to, 1; Age related macular degeneration 4	2024-02-24	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001308868	SCV003831618	uncertain significance	not provided	2019-10-24	criteria provided, single submitter	clinical testing
GeneDx	RCV001308868	SCV004028120	uncertain significance	not provided	2023-08-17	criteria provided, single submitter	clinical testing	Identified in the heterozygous state in an individual with membranoproliferative glomerulonephritis who later developed atypical uremic syndrome; this individual's father was heterozygous but unaffected. Both individuals were also homozygous for CFH disease risk polymorphisms (Gnappi et al., 2012); Identified in the heterozygous state in individuals with age-related macular degeneration, and also present in control individuals (Ng et al., 2008; Duvvari et al., 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22669321, 25814826, 18421087, 34189567)
Ambry Genetics	RCV003346448	SCV004050836	uncertain significance	Inborn genetic diseases	2023-08-25	criteria provided, single submitter	clinical testing	The c.647T>C (p.I216T) alteration is located in exon 6 (coding exon 6) of the CFH gene. This alteration results from a T to C substitution at nucleotide position 647, causing the isoleucine (I) at amino acid position 216 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Genome-Nilou Lab	RCV003449878	SCV004180738	uncertain significance	Hemolytic uremic syndrome, atypical, susceptibility to, 1	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003449881	SCV004180739	uncertain significance	Age related macular degeneration 4	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003449880	SCV004180740	uncertain significance	Basal laminar drusen	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003449879	SCV004180741	uncertain significance	Factor H deficiency	2023-04-11	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001308868	SCV001741222	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001308868	SCV001974751	uncertain significance	not provided		no assertion criteria provided	clinical testing