chr11-57614475-G-A

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

10
7
2

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]

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 rank MANE Protein UniProt
SERPING1NM_000062.3 linkc.1397G>A p.Arg466His missense_variant Exon 8 of 8 ENST00000278407.9 NP_000053.2 P05155-1E9KL26
SERPING1NM_001032295.2 linkc.1397G>A p.Arg466His missense_variant Exon 7 of 7 NP_001027466.1 P05155-1E9KL26

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SERPING1ENST00000278407.9 linkc.1397G>A p.Arg466His missense_variant Exon 8 of 8 1 NM_000062.3 ENSP00000278407.4 P05155-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461718
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
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.:
32

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
Jul 24, 2019
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

-
Department of Immunology and Histocompatibility, University of Thessaly
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Mar 26, 2024
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Pathogenic:2
Jul 06, 2020
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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) -

May 20, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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). This variant is not present in population databases (gnomAD no frequency). 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 also known as p.Arg444His. ClinVar contains an entry for this variant (Variation ID: 3946). 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. 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. For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases Pathogenic:1
Oct 27, 2015
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Apr 14, 2022
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary C1 esterase inhibitor deficiency - dysfunctional factor Pathogenic:1
Feb 25, 1989
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.60
BayesDel_addAF
Pathogenic
0.31
D
BayesDel_noAF
Pathogenic
0.20
CADD
Pathogenic
28
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.85
D;.;.;.;D
Eigen
Uncertain
0.35
Eigen_PC
Uncertain
0.33
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.88
D;D;D;D;D
M_CAP
Pathogenic
0.38
D
MetaRNN
Pathogenic
0.91
D;D;D;D;D
MetaSVM
Uncertain
0.74
D
MutationAssessor
Pathogenic
3.4
M;.;.;.;.
PrimateAI
Benign
0.41
T
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
D
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.

Other links and lift over

dbSNP: rs121907948; hg19: chr11-57381948; COSMIC: COSV105843942; API