rs121907948

chr11-57614475-G-Achr11-57614475-G-Cchr11-57614475-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

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. R466S) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SERPING1 NM_000062.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:1
• Conservation: PhyloP100: 6.21

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain 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 chr11-57614474-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 3947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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: {Pathogenic=6, Uncertain_significance=1}. Variant chr11-57614475-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPING1	NM_000062.3	c.1397G>A	p.Arg466His	missense_variant	8/8	ENST00000278407.9
SERPING1	NM_001032295.2	c.1397G>A	p.Arg466His	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPING1	ENST00000278407.9	c.1397G>A	p.Arg466His	missense_variant	8/8	1	NM_000062.3	P2

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

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:7 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary angioedema type 1 Pathogenic:2 Uncertain: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	Invitae	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	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;.;.;.;.
MutationTaster	Benign	1.0	A;A;A;A;A
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

Other links and lift over

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