VCV001745353.5 - ClinVar

NM_000062.3(SERPING1):c.51+3A>G

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.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000062.3(SERPING1):c.51+3A>G

Variation ID: 1745353 Accession: VCV001745353.5

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q12.1 11: 57598324 (GRCh38) [ NCBI UCSC ] 11: 57365797 (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	Nov 29, 2022	May 1, 2024	Aug 10, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000062.3:c.51+3A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_001032295.2:c.51+3A>G		intron variant
NC_000011.10:g.57598324A>G
NC_000011.9:g.57365797A>G
NG_009625.1:g.5771A>G
LRG_105:g.5771A>G
LRG_105t1:c.51+3A>G

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000011.10:57598323:A:G

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.
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Apr 8, 2016	RCV002335998.2
not provided	Pathogenic (1)	criteria provided, single submitter	Aug 10, 2023	RCV003096615.3

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.
Pathogenic (Aug 10, 2023)	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: SCV003440401.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 15971231‚ 16470590‚ 24456027‚ 17576681‚ 9536098 Comment: This sequence change falls in intron 2 of the SERPING1 gene. It does not directly change the encoded amino acid sequence of the SERPING1 protein. … (more) This sequence change falls in intron 2 of the SERPING1 gene. It does not directly change the encoded amino acid sequence of the SERPING1 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with hereditary angioedema (PMID: 15971231, 16470590, 24456027). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1745353). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing resulting in multiple RNA products (PMID: 16470590). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Apr 08, 2016)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002644626.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (4) PubMed: 15971231‚ 16470590‚ 21864911‚ 24456027 Comment: The c.51+3A>G intronic pathogenic mutation results from an A to G substitution 3 nucleotides after coding exon 1 in the SERPING1 gene. This mutation was … (more) The c.51+3A>G intronic pathogenic mutation results from an A to G substitution 3 nucleotides after coding exon 1 in the SERPING1 gene. This mutation was first identified in two unrelated families with hereditary angiodema (HAE) and reportedly segregated with disease (Roche O et al. Hum. Mutat. 2005; 26:135-44). In another study, three members of an Italian HAE family were heterozygous for this mutation (Bafunno V, Ann. Hum. Genet. 2014 Mar; 78(2):73-82). In addition, functional in vitro studies have found this alteration results in skipping of exon 2 in some transcripts; however, normal transcripts are also produced in this assay (Duponchel C et al. Hum. Mutat. 2006; 27:295-6; López-Lera A et al. Mol. Immunol. 2011; 49:18-27). Based on supporting evidence, c.51+3A>G is interpreted as a disease-causing mutation. (less)

Comment:

This sequence change falls in intron 2 of the SERPING1 gene. It does not directly change the encoded amino acid sequence of the SERPING1 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with hereditary angioedema (PMID: 15971231, 16470590, 24456027). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1745353). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing resulting in multiple RNA products (PMID: 16470590). For these reasons, this variant has been classified as Pathogenic.

Comment:

The c.51+3A>G intronic pathogenic mutation results from an A to G substitution 3 nucleotides after coding exon 1 in the SERPING1 gene. This mutation was first identified in two unrelated families with hereditary angiodema (HAE) and reportedly segregated with disease (Roche O et al. Hum. Mutat. 2005; 26:135-44). In another study, three members of an Italian HAE family were heterozygous for this mutation (Bafunno V, Ann. Hum. Genet. 2014 Mar; 78(2):73-82). In addition, functional in vitro studies have found this alteration results in skipping of exon 2 in some transcripts; however, normal transcripts are also produced in this assay (Duponchel C et al. Hum. Mutat. 2006; 27:295-6; López-Lera A et al. Mol. Immunol. 2011; 49:18-27). Based on supporting evidence, c.51+3A>G is interpreted as a disease-causing mutation.

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 of the c1 inhibitor gene in a cohort of Italian patients with hereditary angioedema: description of nine novel mutations.	Bafunno V	Annals of human genetics	2014	PMID: 24456027
SERPING1 mutations in 59 families with hereditary angioedema.	López-Lera A	Molecular immunology	2011	PMID: 21864911
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.	Buratti E	Nucleic acids research	2007	PMID: 17576681
Functional analysis of splicing mutations and of an exon 2 polymorphic variant of SERPING1/C1NH.	Duponchel C	Human mutation	2006	PMID: 16470590
Hereditary angioedema: the mutation spectrum of SERPING1/C1NH in a large Spanish cohort.	Roche O	Human mutation	2005	PMID: 15971231
Statistical features of human exons and their flanking regions.	Zhang MQ	Human molecular genetics	1998	PMID: 9536098

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.51+3A>G

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...