VCV002036707.2 - ClinVar

NM_000020.3(ACVRL1):c.1408dup (p.Glu470fs)

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.

(1)

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, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000020.3(ACVRL1):c.1408dup (p.Glu470fs)

Variation ID: 2036707 Accession: VCV002036707.2

Type and length

Duplication, 1 bp

Location

Cytogenetic: 12q13.13 12: 51920786-51920787 (GRCh38) [ NCBI UCSC ] 12: 52314570-52314571 (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	Feb 20, 2024	Oct 25, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000020.3:c.1408dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000011.2:p.Glu470fs	frameshift
NM_001077401.2:c.1408dup	NP_001070869.1:p.Glu470fs	frameshift
NM_001406487.1:c.1408dup	NP_001393416.1:p.Glu470Glyfs	frameshift
NM_001406490.1:c.1252dup	NP_001393419.1:p.Glu418Glyfs	frameshift
NM_001406491.1:c.1096dup	NP_001393420.1:p.Glu366Glyfs	frameshift
NM_001406492.1:c.1096dup	NP_001393421.1:p.Glu366Glyfs	frameshift
NM_001406494.1:c.898dup	NP_001393423.1:p.Glu300Glyfs	frameshift
NM_001406495.1:c.844dup	NP_001393424.1:p.Glu282Glyfs	frameshift
NC_000012.12:g.51920789dup
NC_000012.11:g.52314573dup
NG_009549.1:g.18372dup
LRG_543:g.18372dup
LRG_543t1:c.1408dup	LRG_543p1:p.Glu470Glyfs

... more HGVS ... less HGVS

Protein change

E470fs

Other names

Canonical SPDI

NC_000012.12:51920786:GGG:GGGG

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.
ACVRL1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	1010	1021

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 (1)	criteria provided, single submitter	Oct 25, 2022	RCV002899347.3

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 (Oct 25, 2022)	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: SCV003242672.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024	Publications: PubMed (2) PubMed: 18498373‚ 29650961 Comment: This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu470Glyfs24) in the ACVRL1 gene. … (more) This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu470Glyfs24) in the ACVRL1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 34 amino acid(s) of the ACVRL1 protein. This premature translational stop signal has been observed in individual(s) with hereditary hemorrhagic telangiectasia (Invitae). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the ACVRL1 protein in which other variant(s) (p.Arg484Leu) have been determined to be pathogenic (PMID: 18498373, 29650961; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. (less)

Comment:

This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu470Glyfs*24) in the ACVRL1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 34 amino acid(s) of the ACVRL1 protein. This premature translational stop signal has been observed in individual(s) with hereditary hemorrhagic telangiectasia (Invitae). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the ACVRL1 protein in which other variant(s) (p.Arg484Leu) have been determined to be pathogenic (PMID: 18498373, 29650961; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing.

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
Identification of rare sequence variation underlying heritable pulmonary arterial hypertension.	Gräf S	Nature communications	2018	PMID: 29650961
Detection of a significant association between mutations in the ACVRL1 gene and hepatic involvement in German patients with hereditary haemorrhagic telangiectasia.	Brakensiek K	Clinical genetics	2008	PMID: 18498373

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000020.3(ACVRL1):c.1408dup (p.Glu470fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...