11-57614474-C-T

Variant names:

• chr11-57614474-C-T
• rs28940870
• NM_000062.3:c.1396C>T

Variant summary

Our verdict is Pathogenic. The variant received 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. R466H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SERPING1 NM_000062.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 3.23
• Publications: 28 publications found

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 Gene-Disease associations (from GenCC):

• hereditary angioedema with C1Inh deficiency

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• C1 inhibitor deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary angioedema type 1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary angioedema type 2

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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 chr11-57614475-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 3946.
• 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar as Pathogenic. Clinvar id is 3947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPING1	ENST00000278407.9	c.1396C>T	p.Arg466Cys	missense_variant	Exon 8 of 8	1	NM_000062.3	ENSP00000278407.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4 Other:1

Mar 19, 2024

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Nov 16, 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 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). Invitae Evidence 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 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, 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. -

Dec 13, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Sep 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SERPING1: PM1, PM2, PM5, PS4:Moderate, PP1, PP4 -

Hereditary angioedema type 1 Pathogenic:3

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed missense variant c.1396C>T(p.Arg466Cys) in SERPING1 gene has been reported previously in heterozygous state in multiple individuals individual(s) with hereditary angioedema (Andrejević S, et al., 2015; Cagini N, et al., 2016; Nabilou S, et al., 2022). Other variants (p.Arg466Pro, p.Arg466His, p.Arg466Leu) affecting the same position have been reported to be pathogenic/likely pathogenic in teh ClinVar database (Cagini N, et al., 2023). This variant is absent in the gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic by multiple submitters. The amino acid Arg at position 466 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen - Possibly damaging, SIFT – Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The residue is conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

Dec 12, 2018

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Department of Immunology and Histocompatibility, University of Thessaly

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 11, 2021

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	0.84
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;.;.;.;.
PhyloP100		3.2
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
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs28940870; hg19: chr11-57381947;