VCV002137097.3 - ClinVar

NM_000062.3(SERPING1):c.810CAA[2] (p.Asn272del)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(2)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Likely pathogenic(1); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000062.3(SERPING1):c.810CAA[2] (p.Asn272del)

Variation ID: 2137097 Accession: VCV002137097.3

Type and length

Microsatellite, 3 bp

Location

Cytogenetic: 11q12.1 11: 57606134-57606136 (GRCh38) [ NCBI UCSC ] 11: 57373607-57373609 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Feb 8, 2023	Sep 1, 2024	Aug 9, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000062.3:c.810CAA[2] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000053.2:p.Asn272del	inframe deletion
NM_000062.3:c.816_818del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001032295.2:c.810CAA[2]	NP_001027466.1:p.Asn272del	inframe deletion
NC_000011.10:g.57606134CAA[2]
NC_000011.9:g.57373607CAA[2]
NG_009625.1:g.13581CAA[2]
LRG_105:g.13581CAA[2]
LRG_105t1:c.810_812CAA[2]	LRG_105p1:p.Asn272del

... more HGVS ... less HGVS

Protein change

N272del

Other names

Canonical SPDI

NC_000011.10:57606133:CAACAACAA:CAACAA

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
SERPING1		-	-	GRCh38 GRCh37	724	741

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Uncertain significance (1)	criteria provided, single submitter	Nov 11, 2022	RCV003037394.3
Hereditary angioedema type 1	Likely pathogenic (1)	criteria provided, single submitter	Aug 9, 2024	RCV004698574.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Nov 11, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003439867.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 7937817‚ 22994404 Comment: In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant … (more) In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant is also known as c.813_815delCAA. This variant has been observed in individuals with hereditary angioedema (PMID: 7937817, 22994404; Invitae). This variant is not present in population databases (gnomAD no frequency). This variant, c.816_818del, results in the deletion of 1 amino acid(s) of the SERPING1 protein (p.Asn272del), but otherwise preserves the integrity of the reading frame. (less)
Likely pathogenic (Aug 09, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Hereditary angioedema type 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	DNA-diagnostics Laboratory, Research Centre For Medical Genetics Accession: SCV005200126.1 First in ClinVar: Sep 01, 2024 Last updated: Sep 01, 2024	Publications: PubMed (2) PubMed: 7937817‚ 8755917 DOI: 10.1002/humu.20197 DOI: 10.1002/humu.20197 DOI: 10.1016/j.molimm.2011.07.010 DOI: 10.1016/j.molimm.2011.07.010 DOI: 10.1111/all.12024 DOI: 10.1111/all.12024 DOI: 10.1007/s10875-015-0222-9 DOI: 10.1007/s10875-015-0222-9 DOI: 10.1002/humu.23917 DOI: 10.1002/humu.23917 Comment: The pathogenic or likely pathogenic SERPING1 gene variants are detected in >90% of the HAE1/2 families and in >80% of the total HAE families (e.g., … (more) The pathogenic or likely pathogenic SERPING1 gene variants are detected in >90% of the HAE1/2 families and in >80% of the total HAE families (e.g., DOI: 10.1016/j.molimm.2008.05.007, 10.1159/2F000138883, 10.1016/j.molimm.2011.07.010). In our study, the heterozygous c.816_818del (p.Asn272del) variant in SERPING1 was observed in 1 HAE1/2 patient with a family HAE history. The same variant has previously been reported at least in 12 HAE1 cases (PMID: 7937817, 8755917, DOI: 10.1002/humu.20197, 10.1016/j.molimm.2011.07.010, 10.1111/all.12024, 10.1007/s10875-015-0222-9, 10.1002/humu.23917). According to our observation and published information , the c.816_818del variant in SERPING1 meets ACMG/ClinGen SVI guidance criteria to be classified as likely pathogenic: PP4_Str, PM4, PS4_Mod, PM2_Sup (less) Sex: male Geographic origin: Russia

Comment:

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant is also known as c.813_815delCAA. This variant has been observed in individuals with hereditary angioedema (PMID: 7937817, 22994404; Invitae). This variant is not present in population databases (gnomAD no frequency). This variant, c.816_818del, results in the deletion of 1 amino acid(s) of the SERPING1 protein (p.Asn272del), but otherwise preserves the integrity of the reading frame.

Comment:

The pathogenic or likely pathogenic SERPING1 gene variants are detected in >90% of the HAE1/2 families and in >80% of the total HAE families (e.g., DOI: 10.1016/j.molimm.2008.05.007, 10.1159/2F000138883, 10.1016/j.molimm.2011.07.010). In our study, the heterozygous c.816_818del (p.Asn272del) variant in SERPING1 was observed in 1 HAE1/2 patient with a family HAE history. The same variant has previously been reported at least in 12 HAE1 cases (PMID: 7937817, 8755917, DOI: 10.1002/humu.20197, 10.1016/j.molimm.2011.07.010, 10.1111/all.12024, 10.1007/s10875-015-0222-9, 10.1002/humu.23917). According to our observation and published information , the c.816_818del variant in SERPING1 meets ACMG/ClinGen SVI guidance criteria to be classified as likely pathogenic: PP4_Str, PM4, PS4_Mod, PM2_Sup

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Mutational spectrum and geno-phenotype correlation in Chinese families with hereditary angioedema.	Xu YY	Allergy	2012	PMID: 22994404
Exhaustive mutation scanning by fluorescence-assisted mismatch analysis discloses new genotype-phenotype correlations in angiodema.	Verpy E	American journal of human genetics	1996	PMID: 8755917
A cluster of mutations within a short triplet repeat in the C1 inhibitor gene.	Bissler JJ	Proceedings of the National Academy of Sciences of the United States of America	1994	PMID: 7937817
-	-	-	-	DOI: 10.1002/humu.20197
-	-	-	-	DOI: 10.1002/humu.23917
-	-	-	-	DOI: 10.1007/s10875-015-0222-9
-	-	-	-	DOI: 10.1016/j.molimm.2011.07.010
-	-	-	-	DOI: 10.1111/all.12024

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000062.3(SERPING1):c.810CAA[2] (p.Asn272del)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...