chr1-196747245-C-T

Position:

chr1-196747245-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PS1_ModeratePM1PM2PP3_ModeratePP5

The NM_000186.4(CFH):c.3628C>T(p.Arg1210Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000137 in 1,613,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

CFH
NM_000186.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:3O:3

Conservation

PhyloP100: -4.58

Variant links:

Genes affected

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]

CFH links:

ENSG00000289697 (HGNC:):

ENSG00000289697 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PS1

Transcript NM_000186.4 (CFH) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_000186.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.921

PP5

Variant 1-196747245-C-T is Pathogenic according to our data. Variant chr1-196747245-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 16558.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, not_provided=1, Pathogenic=5}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFH	NM_000186.4 linkuse as main transcript	c.3628C>T	p.Arg1210Cys	missense_variant	22/22	ENST00000367429.9	NP_000177.2	P08603A0A024R962

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFH	ENST00000367429.9 linkuse as main transcript	c.3628C>T	p.Arg1210Cys	missense_variant	22/22	1	NM_000186.4	ENSP00000356399.4		P08603
ENSG00000289697	ENST00000696032.1 linkuse as main transcript	c.3580+48C>T		intron_variant				ENSP00000512341.1		A0A8Q3SIA1

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000353

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000143

AC:

AN:

251244

Hom.:

AF XY:

0.000147

AC XY:

AN XY:

135776

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000282

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000133

AC:

194

AN:

1461694

Hom.:

Cov.:

AF XY:

0.000136

AC XY:

AN XY:

727160

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000158

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000177

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000353

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00109

Hom.:

Bravo

AF:

0.000230

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000173

AC:

EpiCase

AF:

0.000763

EpiControl

AF:

0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:3Other:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 18, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 20, 2024	PS3, PS4 -

Age related macular degeneration 4

Pathogenic:1Other:1

risk factor, no assertion criteria provided	literature only	OMIM	Jul 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 09, 2018	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. -

Hemolytic uremic syndrome, atypical, susceptibility to, 1

Other:2

risk factor, no assertion criteria provided	literature only	OMIM	Jul 01, 2015	- -
not provided, no classification provided	literature only	GeneReviews	-	Common pathogenic variant [Martinez-Barricarte et al 2008] -

Factor H deficiency;C0730295:Basal laminar drusen;C1853147:Age related macular degeneration 4;C2749604:Hemolytic uremic syndrome, atypical, susceptibility to, 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jun 30, 2021

- -

Factor H deficiency

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2015

- -

Atypical hemolytic-uremic syndrome

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Sydney Genome Diagnostics, Children's Hospital Westmead

Oct 25, 2018

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. -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2023

- -

Kidney disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 16, 2017

- -

CFH-Related Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type II

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 16, 2017

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. -

Basal laminar drusen

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 16, 2017

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.36

CADD

Benign

6.9

DANN

Benign

0.95

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.0016

LIST_S2

Benign

0.38

M_CAP

Benign

0.025

MetaRNN

Pathogenic

0.92

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.75

REVEL

Benign

0.28

Sift

Benign

0.060

Sift4G

Uncertain

0.015

Vest4

0.67

MVP

0.95

MPC

2.0

ClinPred

0.049

GERP RS

-7.7

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over