11-57614474-C-T

Position:

• chr11-57614474-C-T

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.1396C>T​(p.Arg466Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). 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)
• Consequence: SERPING1 NM_000062.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 3.23

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 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, 0.952
• PP5: Variant 11-57614474-C-T is Pathogenic according to our data. 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. Variant chr11-57614474-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPING1	NM_000062.3	c.1396C>T	p.Arg466Cys	missense_variant	8/8	ENST00000278407.9	NP_000053.2
SERPING1	NM_001032295.2	c.1396C>T	p.Arg466Cys	missense_variant	7/7		NP_001027466.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERPING1	ENST00000278407.9	c.1396C>T	p.Arg466Cys	missense_variant	8/8	1	NM_000062.3	ENSP00000278407	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 13, 2022	Not observed in large population cohorts (gnomAD); 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: 27116602, 23437219, 23123409, 24456027, 26154504, 26751894, 26535898, 2563376, 18758157, 18586324, 25258140, 15971231, 22994404, 26809362, 26812872, 27826968, 21864911, 28302171, 29753808, 30556912, 32896191) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 09, 2023	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, 23437219, 30556912). 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. 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 sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 466 of the SERPING1 protein (p.Arg466Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary angioedema (PMID: 2563376, 18586324, 18758157, 23437219, 26812872, 30556912). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg444Cys. ClinVar contains an entry for this variant (Variation ID: 3947). -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Mar 19, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	SERPING1: PM1, PM2, PM5, PS4:Moderate, PP1, PP4 -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -

Hereditary angioedema type 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Dec 12, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Immunology and Histocompatibility, University of Thessaly	-	The c.1396C>T (p.Arg466Cys) variant has been previously reported in association with with hereditary angioedema in the literature (Skriver et al., 1989; Freiberger et al., 2002; Roche et al., 2005; Gosswein et al., 2008; Pappalardo et al., 2008; Lopez-Lera et al., 2011; Xu et al., 2012; Cagini et al., 2016, 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 4 C1-INH-HAE Type II patients of a Greek family (2 male and 2 female) and 1 unrelated female patient with HAE type II and no family history. Skriver et al., 1989 presented conflicting observations about the inhibitory activity of C1-INH and consequently about the pathogenicity of the mutation. Missense variants changing the same residue [c.1397G>A (p.Arg466His), 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 angioneurotic edema. Taking all the above into account and according to ACMG Guidelines, 2015 (Criteria: PS1, PS4, PM2, PP1, PP2, PP4), the variant is considered pathogenic. -

Hereditary C1 esterase inhibitor deficiency - dysfunctional factor Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 11, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D;.;.;.;D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.90	D;D;D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Uncertain	2.9	M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-7.0	D;D;D;D;D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		0.92	P;.;.;.;.
Vest4		0.67
MutPred		0.74		.;.;Gain of catalytic residue at R471 (P = 0.0436);.;.;
MVP		0.95
MPC		1.2
ClinPred		0.99	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.96

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: rs28940870; hg19: chr11-57381947;