rs281875170

chr11-57600377-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000062.3(SERPING1):c.550G>A(p.Gly184Arg) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 14/25 in silico tools predict a damaging outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G184W) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SERPING1 NM_000062.3 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 5.17

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a disulfide_bond (size 75) in uniprot entity IC1_HUMAN there are 69 pathogenic changes around while only 1 benign (99%) 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 chr11-57600377-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2137092.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-57600377-G-A is Pathogenic according to our data. Variant chr11-57600377-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68253.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-57600377-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPING1	NM_000062.3	c.550G>A	p.Gly184Arg	missense_variant, splice_region_variant	3/8	ENST00000278407.9
SERPING1	NM_001032295.2	c.550G>A	p.Gly184Arg	missense_variant, splice_region_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPING1	ENST00000278407.9	c.550G>A	p.Gly184Arg	missense_variant, splice_region_variant	3/8	1	NM_000062.3	P2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 13, 2016	The G184R missense variant in the SERPING1 gene has been frequently reported in association with hereditary angiodema (Roche et al., 2005; Verpy et al., 1996; Gosswein et al., 2008). G184R was not observed in approximately 6400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This non-conservative amino acid substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not G184R is damaging to the protein structure/function; the variant affects a non-canonical splice donor site in intron 3, and may cause abnormal gene splicing with skipping of exon 3 (de la Cruz et al., 2012). Functional studies show that healthy controls have both the full SERPING1 protein and low levels of a protein variant missing exon 3. The presence of G184R disproportionately increases the percentage of exon 3 skipping variant while decreasing the overall amount of SERPING1 protein (de la Cruz et al., 2012). Missense variants in the same (G184E) and nearby residues (T179I, L183P, A185P, T189N) have been reported in the Human Gene Mutation Database in association with hereditary angiodema (Stenson et al., 2014), supporting the functional importance of this region of the protein. -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Apr 30, 2022	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 184 of the SERPING1 protein (p.Gly184Arg). This variant also falls at the last nucleotide of exon 3, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary angioedema type1 or type 2 (PMID: 18586324, 20804470, 21832835, 28359783). This variant is also known as 2694G>A (p.Gly162Arg). ClinVar contains an entry for this variant (Variation ID: 68253). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SERPING1 function (PMID: 30398465). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 28359783). This variant disrupts the p.Gly184 amino acid residue in SERPING1. Other variant(s) that disrupt this residue have been observed in individuals with SERPING1-related conditions (PMID: 28359783), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2021	- -

Hereditary angioedema type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Department of Immunology and Histocompatibility, University of Thessaly

-

The c.550G>A (p.Gly184Arg) mutation in the SERPING1 gene has been previously reported in association with hereditary angioedema in the literature (Roche et al., 2005; Verpy et al., 1996; Gosswein et al., 2008; Kesim et al., 2011; 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 2 C1-INH HAE Type I male patients of a Greek family. Two missense mutations, changing the same residue, c.550G>C, p.Gly184Arg and c.551G>A, p.Gly184Glu have been previously associated with hereditary angioedema by Roche O et al. (2005) and Zuraw et al (2000). Taking all the above into account and according to ACMG Guidelines, 2015 (Criteria: PS1, PS4, PM2, PP1, PP2, PP4), the variant is considered pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D;.;.;.;D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.86	D;D;D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.6	H;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-7.2	D;D;D;D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D
Polyphen		1.0	D;.;.;.;D
Vest4		0.91
MutPred		0.97		.;.;.;.;Gain of catalytic residue at G218 (P = 0.1604);
MVP		0.97
MPC		1.1
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.98
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.53		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.53		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs281875170; hg19: chr11-57367850; COSMIC: COSV53542890; COSMIC: COSV53542890;