rs121907948

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5

The NM_000062.3(SERPING1):c.1397G>A(p.Arg466His) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R466L) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SERPING1
NM_000062.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:1

Conservation

PhyloP100: 6.21

Variant links:

Genes affected

SERPING1 (HGNC:1228): (serpin family G member 1) This gene encodes a highly glycosylated plasma protein involved in the regulation of the complement cascade. Its encoded protein, C1 inhibitor, inhibits activated C1r and C1s of the first complement component and thus regulates complement activation. It is synthesized in the liver, and its deficiency is associated with hereditary angioneurotic oedema (HANE). Alternative splicing results in multiple transcript variants encoding the same isoform. [provided by RefSeq, May 2020]

SERPING1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a site Reactive bond for chymotrypsin (size 1) in uniprot entity IC1_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_000062.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.908

PP5

Variant 11-57614475-G-A is Pathogenic according to our data. Variant chr11-57614475-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 3946.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=6}. Variant chr11-57614475-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPING1	NM_000062.3 linkuse as main transcript	c.1397G>A	p.Arg466His	missense_variant	8/8	ENST00000278407.9	NP_000053.2
SERPING1	NM_001032295.2 linkuse as main transcript	c.1397G>A	p.Arg466His	missense_variant	7/7		NP_001027466.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERPING1	ENST00000278407.9 linkuse as main transcript	c.1397G>A	p.Arg466His	missense_variant	8/8	1	NM_000062.3	ENSP00000278407	P2	P05155-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461718

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727172

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary angioedema type 1

Pathogenic:2Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 24, 2019	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Immunology and Histocompatibility, University of Thessaly	-	The c.1397G>A (p.Arg466His) variant has been previously reported in association with hereditary angioedema in the literature (Ariga et al., 1989; Freiberger et al., 2002; Cumming et al., 2003; Gosswein et al., 2008; Faiyaz-Ul-Haque et al., 2010, Loules et al., 2018), in HAE database (http://hae.enzim.hu/detail.php?id=43) and in ClinVar database. The variant has not been detected in approximately 120000 individuals of the Exome Aggregation Consortium (ExAC) database, indicating that it is not a common variant. It was detected by our laboratory in 7 C1-INH-HAE Type II patients of a Greek family (4 male and 3 female) and 1 unrelated male patient with family history for the disease. According to functional studies concerning the reactive-centre region of C1-INH the variant causes loss of trypsin sensitivity and lowers the activity level of the protein (Aulak et al., 1988). Missense variants in the same residue [c.1396C>T (p.Arg466Cys), c.1396C>A (p.Arg466Ser), c.1396C>G (p.Arg466Gly), c.1397G>C (p.Arg466Pro), c.1397G>T (p.Arg466Leu)] and in nearby residues [c.1394C>T (p.Ala465Val)] have been previously reported in association with hereditary angioedema. Taking all the above into account and according to ACMG Guidelines, 2015 (Criteria: PS1, PS3, PS4, PM2, PP1, PP2, PP4), the variant is considered pathogenic. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 06, 2020	Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20804470, 2894352, 28302171, 10719305, 12402344, 14569137, 27617473, 18758157, 24456027, 2563376, 3178731, 23437219, 11933207, 19752569, 29753808, 30556912) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 12, 2022	Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SERPING1 protein function. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg466 amino acid residue in SERPING1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2563376, 18586324, 18758157, 23437219, 26812872). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 3946). This variant is also known as p.Arg444His. This missense change has been observed in individuals with hereditary angioedema type 2 (PMID: 2563376, 23437219, 30556912). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 466 of the SERPING1 protein (p.Arg466His). -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 27, 2015

The p.R466H pathogenic mutation (also known as c.1397G>Aand p.R44H), located in coding exon 7 of the SERPING1 gene, results from a G to A substitution at nucleotide position 1397. The arginine at codon 466 is replaced by histidine, an amino acid with highly similar properties. This variant has been observed in several individuals with a clinical diagnosis of hereditary angioedema (Aulak KS, Biochem. J. 1988 Jul; 253(2):615-8. Skriver K, J. Biol. Chem. 1989 Feb; 264(6):3066-71). In addition, C1 inhibitor activity levels were decreased in affected patients with this variant, even though serum levels were normal (Rijavec M, PLoS ONE 2013 ; 8(2):e56712). Multiple alterations at the same amino acid have also been reported (Aulak KS et al, FEBS Lett. 1990 Jun; 266(1-2):13-6; Frangi D et al, FEBS Lett. 1992 Apr; 301(1):34-6; Blanch A et al, Hum. Mutat. 2002 Nov; 20(5):405-6; Gösswein T et al, Cytogenet. Genome Res. 2008 ; 121(3-4):181-8; Rijavec M, PLoS ONE 2013 ; 8(2):e56712). Based on the available evidence, p.R466H is classified as a pathogenic mutation. -

C1 inhibitor deficiency;C2717906:Hereditary angioedema type 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 14, 2022

- -

Hereditary C1 esterase inhibitor deficiency - dysfunctional factor

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 25, 1989

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.85

D;.;.;.;D

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.88

D;D;D;D;D

M_CAP

Pathogenic

0.38

MetaRNN

Pathogenic

0.91

D;D;D;D;D

MetaSVM

Uncertain

0.74

MutationAssessor

Pathogenic

3.4

M;.;.;.;.

MutationTaster

Benign

1.0

A;A;A;A;A

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-4.3

D;D;D;D;D

REVEL

Pathogenic

0.67

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Uncertain

0.0040

D;D;D;D;D

Polyphen

0.67

P;.;.;.;.

Vest4

0.55

MutPred

0.71

.;.;Gain of sheet (P = 0.0827);.;.;

MVP

0.91

MPC

1.1

ClinPred

0.99

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.98

gMVP

0.90

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

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