VCV000236552.23 - ClinVar

NM_000020.3(ACVRL1):c.693CTC[1] (p.Ser233del)

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.

(6)

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_000020.3(ACVRL1):c.693CTC[1] (p.Ser233del)

Variation ID: 236552 Accession: VCV000236552.23

Type and length

Microsatellite, 3 bp

Location

Cytogenetic: 12q13.13 12: 51914506-51914508 (GRCh38) [ NCBI UCSC ] 12: 52308290-52308292 (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	Jul 16, 2016	May 1, 2024	Dec 16, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000020.3:c.693CTC[1] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000011.2:p.Ser233del	inframe deletion
NM_000020.2:c.696_698del
NM_000020.2:c.696_698delCTC
NM_001077401.2:c.693CTC[1]	NP_001070869.1:p.Ser233del	inframe deletion
NC_000012.12:g.51914506CTC[1]
NC_000012.11:g.52308290CTC[1]
NG_009549.1:g.12089CTC[1]
LRG_543:g.12089CTC[1]

... more HGVS ... less HGVS

Protein change

S233del

Other names

Canonical SPDI

NC_000012.12:51914505:CTCCTC:CTC

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

ClinGen: CA254369 OMIM: 601284.0003 dbSNP: rs387906391 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.
ACVRL1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	1011	1022

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.
Telangiectasia, hereditary hemorrhagic, type 2	Pathogenic (2)	criteria provided, single submitter	Dec 16, 2023	RCV000230219.10
not specified	Pathogenic (1)	criteria provided, single submitter	Aug 16, 2016	RCV000506933.9
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Nov 25, 2022	RCV001507805.6
Cardiovascular phenotype	Pathogenic (1)	criteria provided, single submitter	Dec 13, 2022	RCV002372240.3

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 16, 2016)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000602394.1 First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017
Pathogenic (Dec 16, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Telangiectasia, hereditary hemorrhagic, type 2 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000282681.9 First in ClinVar: Jul 03, 2016 Last updated: Feb 20, 2024	Publications: PubMed (4) PubMed: 8640225‚ 15024723‚ 16752392‚ 21158752 Comment: This variant, c.696_698del, results in the deletion of 1 amino acid(s) of the ACVRL1 protein (p.Ser233del), but otherwise preserves the integrity of the reading frame. … (more) This variant, c.696_698del, results in the deletion of 1 amino acid(s) of the ACVRL1 protein (p.Ser233del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with hereditary hemorrhagic telangiectasia (HHT) (PMID: 8640225, 15024723, 16752392, 21158752; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 236552). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jan 28, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV001713598.1 First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021	Publications: PubMed (9) PubMed: 8717052‚ 8640225‚ 9245985‚ 10767348‚ 15024723‚ 16752392‚ 17576210‚ 19508727‚ 21158752 Comment: PP1_Strong, PS4, PP4, PM4, PM2 Number of individuals with the variant: 2
Pathogenic (Nov 25, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002757188.1 First in ClinVar: Dec 03, 2022 Last updated: Dec 03, 2022	Comment: In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Not observed at significant frequency … (more) In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10767348, 16752392, 21158752, 9245985, 15266205, 8640225, 15024723) (less)
Pathogenic (Dec 13, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002668283.3 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (8) PubMed: 10767348‚ 15024723‚ 15266205‚ 16752392‚ 19508727‚ 21158752‚ 8640225‚ 9245985 Comment: The c.696_698delCTC pathogenic mutation (also known as p.S233del) is located in coding exon 5 of the ACVRL1 gene. This pathogenic mutation results from an in-frame … (more) The c.696_698delCTC pathogenic mutation (also known as p.S233del) is located in coding exon 5 of the ACVRL1 gene. This pathogenic mutation results from an in-frame CTC deletion at nucleotide positions 696 to 698. This results in the in-frame deletion of a serine at codon 233. This pathogenic mutation segregated with disease in a large family affected with hereditary hemorrhagic telangiectasia (HHT); however, there were a few unaffected carriers, which was attributed to incomplete penetrance (Johnson DW et al. Nat. Genet., 1996 Jun;13:189-95). This pathogenic mutation was also observed in an individual that presented with epistaxis, telangiectasias, and a family history of HHT (Bossler AD et al. Hum. Mutat., 2006 Jul;27:667-75). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Pathogenic (Jun 01, 1996)	no assertion criteria provided Method: literature only	TELANGIECTASIA, HEREDITARY HEMORRHAGIC, TYPE 2 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000028938.2 First in ClinVar: Apr 04, 2013 Last updated: Jul 16, 2016	Publications: PubMed (1) PubMed: 8640225 Comment on evidence: In affected members of a family with hereditary hemorrhagic telangiectasia (HHT2; 600376), Johnson et al. (1996) identified a 3-bp deletion (their cDNA nucleotides 696-698) in … (more) In affected members of a family with hereditary hemorrhagic telangiectasia (HHT2; 600376), Johnson et al. (1996) identified a 3-bp deletion (their cDNA nucleotides 696-698) in the ALK1 gene, resulting in deletion of 1 of 2 adjacent serine residues that are conserved in most of the type I TGF-beta receptor family members from mammals to Drosophila. The deletion occurred in the kinase subdomain II. Johnson et al. (1996) also identified this deletion in a few unaffected individuals, all of whom showed the disease haplotype throughout the entire candidate interval; they were presumed to be nonpenetrant for HHT. (less)

Comment:

This variant, c.696_698del, results in the deletion of 1 amino acid(s) of the ACVRL1 protein (p.Ser233del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with hereditary hemorrhagic telangiectasia (HHT) (PMID: 8640225, 15024723, 16752392, 21158752; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 236552). For these reasons, this variant has been classified as Pathogenic.

Comment:

In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10767348, 16752392, 21158752, 9245985, 15266205, 8640225, 15024723)

Comment:

The c.696_698delCTC pathogenic mutation (also known as p.S233del) is located in coding exon 5 of the ACVRL1 gene. This pathogenic mutation results from an in-frame CTC deletion at nucleotide positions 696 to 698. This results in the in-frame deletion of a serine at codon 233. This pathogenic mutation segregated with disease in a large family affected with hereditary hemorrhagic telangiectasia (HHT); however, there were a few unaffected carriers, which was attributed to incomplete penetrance (Johnson DW et al. Nat. Genet., 1996 Jun;13:189-95). This pathogenic mutation was also observed in an individual that presented with epistaxis, telangiectasias, and a family history of HHT (Bossler AD et al. Hum. Mutat., 2006 Jul;27:667-75). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration 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
Molecular diagnosis in hereditary hemorrhagic telangiectasia: findings in a series tested simultaneously by sequencing and deletion/duplication analysis.	McDonald J	Clinical genetics	2011	PMID: 21158752
Mutation analysis of "Endoglin" and "Activin receptor-like kinase" genes in German patients with hereditary hemorrhagic telangiectasia and the value of rapid genotyping using an allele-specific PCR-technique.	Sadick H	BMC medical genetics	2009	PMID: 19508727
Altered endothelial gene expression associated with hereditary haemorrhagic telangiectasia.	Thomas B	European journal of clinical investigation	2007	PMID: 17576210
Novel mutations in ENG and ACVRL1 identified in a series of 200 individuals undergoing clinical genetic testing for hereditary hemorrhagic telangiectasia (HHT): correlation of genotype with phenotype.	Bossler AD	Human mutation	2006	PMID: 16752392
Hereditary hemorrhagic telangiectasia: an overview of diagnosis and management in the molecular era for clinicians.	Bayrak-Toydemir P	Genetics in medicine : official journal of the American College of Medical Genetics	2004	PMID: 15266205
Molecular screening of ALK1/ACVRL1 and ENG genes in hereditary hemorrhagic telangiectasia in France.	Lesca G	Human mutation	2004	PMID: 15024723
Analysis of ALK-1 and endoglin in newborns from families with hereditary hemorrhagic telangiectasia type 2.	Abdalla SA	Human molecular genetics	2000	PMID: 10767348
The activin receptor-like kinase 1 gene: genomic structure and mutations in hereditary hemorrhagic telangiectasia type 2.	Berg JN	American journal of human genetics	1997	PMID: 9245985
Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2.	Johnson DW	Nature genetics	1996	PMID: 8640225
A second locus for hereditary hemorrhagic telangiectasia maps to chromosome 12.	Johnson DW	Genome research	1995	PMID: 8717052

Text-mined citations for rs387906391 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000020.3(ACVRL1):c.693CTC[1] (p.Ser233del)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs387906391 ...