Table 1. Rare germline CFH variants... | American Society of Hematology

Table 1.

Rare germline CFH variants among patients with PNH

UPN	Gene	Variant	Transcript	Status	MAF (%)	CADD score	In vitro functional characterization²³	Summary of the effect	Classification in this report
PNH016	CFH	c.472G>A	p.Val158Ile	Hz	0.018	0.001	yes	Any identified functional defect²⁴	VUS
PNH028	CFH	c.2077G>A	p.Asp693Asn	Hz	0.016	20.8	no	Low FH plasma level	Pathogenic
PNH030	CFI	c.672T>A	p.Asp224Glu	Hz	novel	0.038	yes	Any identified functional defect²⁵	VUS
PNH032	C3	c.664T>A	p.Phe222Ile	Hz	0.005	27.3	no		VUS
PNH032	C3	c.4100T>C	p.Ile1367Thr	Hz	0.081	17.41	no		VUS
PNH032	CFI	c.1246A>C	p.Ile416Leu∗	Hz	0.02	18.64	yes	Significantly reduced expression compared with WT²⁶	Pathogenic
PNH033	CFH	c.3004G>C	p.Gly1002Arg	Hz	0.078	17.45	no	Low FH plasma level with Alternative pathway C3 consumption	Pathogenic
PNH037	CFH	c.2651C>A	p.Ser884Tyr	Hz	0.032	17.24	yes	Any identified functional defect²⁴	VUS
PNH038	CFI	c.1534G>A	p.Gly512Ser	Hz	0.0017	33	yes	Any identified functional defect²⁵	VUS
PNH046	C3	c.4100T>C	p.Ile1367Thr	Hz	0.081	17.41	no		VUS
PNH060	C3	c.749G>T	p.Gly250Val	Hz	novel	19.09	no		VUS
PNH073	CFH	c.1366G>A	p.Glu456Lys	Hz	0.0008	2.658	no	Normal C3 level in plasma	VUS
PNH078	C3	c.1119+1G>A	IVS10+1	Hz	novel	35	no	Splice site variant	Pathogenic
PNH087	CFH	c.2295A>T	p.Leu765Phe	Hz	0.0036	0.035	no	Normal C3 level in plasma	VUS
PNH097	C3	c.3083T>G	p.Leu1028Arg	Hz	novel	26.7	no		VUS
PNH097	CFH	c.472G>A	p.Val158Ile	Hz	0.018	0.001	yes	Any identified functional defect²⁵	VUS
PNH102	CFH	c.2867C>T	p.Thr956Met	Hz	0.1	14.99	yes	Any identified functional defect²⁵	VUS
PNH103	CFH	c.388G>A	p.Asp130Asn	Hz	0.014	22.6	yes	Normal C3 and FH levels in plasma, minor defects in complement regulation²³	Pathogenic
PNH108	C3	c.4100T>C	p.Ile1367Thr	Hz	0.081	17.41	no		VUS

UPN	Gene	Variant	Transcript	Status	MAF (%)	CADD score	In vitro functional characterization²³	Summary of the effect	Classification in this report
PNH016	CFH	c.472G>A	p.Val158Ile	Hz	0.018	0.001	yes	Any identified functional defect²⁴	VUS
PNH028	CFH	c.2077G>A	p.Asp693Asn	Hz	0.016	20.8	no	Low FH plasma level	Pathogenic
PNH030	CFI	c.672T>A	p.Asp224Glu	Hz	novel	0.038	yes	Any identified functional defect²⁵	VUS
PNH032	C3	c.664T>A	p.Phe222Ile	Hz	0.005	27.3	no		VUS
PNH032	C3	c.4100T>C	p.Ile1367Thr	Hz	0.081	17.41	no		VUS
PNH032	CFI	c.1246A>C	p.Ile416Leu∗	Hz	0.02	18.64	yes	Significantly reduced expression compared with WT²⁶	Pathogenic
PNH033	CFH	c.3004G>C	p.Gly1002Arg	Hz	0.078	17.45	no	Low FH plasma level with Alternative pathway C3 consumption	Pathogenic
PNH037	CFH	c.2651C>A	p.Ser884Tyr	Hz	0.032	17.24	yes	Any identified functional defect²⁴	VUS
PNH038	CFI	c.1534G>A	p.Gly512Ser	Hz	0.0017	33	yes	Any identified functional defect²⁵	VUS
PNH046	C3	c.4100T>C	p.Ile1367Thr	Hz	0.081	17.41	no		VUS
PNH060	C3	c.749G>T	p.Gly250Val	Hz	novel	19.09	no		VUS
PNH073	CFH	c.1366G>A	p.Glu456Lys	Hz	0.0008	2.658	no	Normal C3 level in plasma	VUS
PNH078	C3	c.1119+1G>A	IVS10+1	Hz	novel	35	no	Splice site variant	Pathogenic
PNH087	CFH	c.2295A>T	p.Leu765Phe	Hz	0.0036	0.035	no	Normal C3 level in plasma	VUS
PNH097	C3	c.3083T>G	p.Leu1028Arg	Hz	novel	26.7	no		VUS
PNH097	CFH	c.472G>A	p.Val158Ile	Hz	0.018	0.001	yes	Any identified functional defect²⁵	VUS
PNH102	CFH	c.2867C>T	p.Thr956Met	Hz	0.1	14.99	yes	Any identified functional defect²⁵	VUS
PNH103	CFH	c.388G>A	p.Asp130Asn	Hz	0.014	22.6	yes	Normal C3 and FH levels in plasma, minor defects in complement regulation²³	Pathogenic
PNH108	C3	c.4100T>C	p.Ile1367Thr	Hz	0.081	17.41	no		VUS

Allelic frequency has been taken from the Genome Aggregation Database (gnomAD). PNH032 carried a pathogenic CFI variant (p.Ile416Leu) and 2 C3 variants of undetermined significance (p.Ile1367Thr and p.Phe222Ile ); PNH097 carried 2 VUS variants in C3 (p.Leu1028Arg) and CFH (p.Val158Ile).

CADD, combined annotation dependent depletion; Hz, heterozygous; VUS, variants of undetermined significance.

∗

The allelic frequency for p.Ile416Leu in the African population is 1.2%.

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