VCV002735869.1 - ClinVar

NM_000020.3(ACVRL1):c.631G>A (p.Gly211Ser)

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.631G>A (p.Gly211Ser)

Variation ID: 2735869 Accession: VCV002735869.1

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12q13.13 12: 51914444 (GRCh38) [ NCBI UCSC ] 12: 52308228 (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 14, 2024	Feb 14, 2024	Jan 16, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000020.3:c.631G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000011.2:p.Gly211Ser	missense
NM_001077401.2:c.631G>A	NP_001070869.1:p.Gly211Ser	missense
NM_001406487.1:c.631G>A	NP_001393416.1:p.Gly211Ser	missense
NM_001406488.1:c.631G>A	NP_001393417.1:p.Gly211Ser	missense
NM_001406489.1:c.631G>A	NP_001393418.1:p.Gly211Ser	missense
NM_001406490.1:c.319G>A	NP_001393419.1:p.Gly107Ser	missense
NM_001406491.1:c.319G>A	NP_001393420.1:p.Gly107Ser	missense
NM_001406492.1:c.319G>A	NP_001393421.1:p.Gly107Ser	missense
NM_001406493.1:c.319G>A	NP_001393422.1:p.Gly107Ser	missense
NM_001406494.1:c.319G>A	NP_001393423.1:p.Gly107Ser	missense
NM_001406495.1:c.67G>A	NP_001393424.1:p.Gly23Ser	missense
NC_000012.12:g.51914444G>A
NC_000012.11:g.52308228G>A
NG_009549.1:g.12027G>A
LRG_543:g.12027G>A
LRG_543t1:c.631G>A	LRG_543p1:p.Gly211Ser

... more HGVS ... less HGVS

Protein change

G107S, G23S, G211S

Other names

Canonical SPDI

NC_000012.12:51914443:G:A

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	1015	1026

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	Jan 16, 2024	RCV003508989.2

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 (Jan 16, 2024)	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: SCV004295064.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 26176610‚ 29743074‚ 25970827 Comment: This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 211 of the ACVRL1 protein (p.Gly211Ser). … (more) This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 211 of the ACVRL1 protein (p.Gly211Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of ACVRL1-related conditions (PMID: 26176610, 29743074). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACVRL1 protein function with a positive predictive value of 95%. This variant disrupts the p.Gly211 amino acid residue in ACVRL1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25970827; Invitae). 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. (less)

Comment:

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 211 of the ACVRL1 protein (p.Gly211Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of ACVRL1-related conditions (PMID: 26176610, 29743074). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACVRL1 protein function with a positive predictive value of 95%. This variant disrupts the p.Gly211 amino acid residue in ACVRL1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25970827; Invitae). 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.

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
Genetic analyses in a cohort of 191 pulmonary arterial hypertension patients.	Yang H	Respiratory research	2018	PMID: 29743074
Mutation analysis in Norwegian families with hereditary hemorrhagic telangiectasia: founder mutations in ACVRL1.	Heimdal K	Clinical genetics	2016	PMID: 25970827
Functional and splicing defect analysis of 23 ACVRL1 mutations in a cohort of patients affected by Hereditary Hemorrhagic Telangiectasia.	Alaa El Din F	PloS one	2015	PMID: 26176610

Text-mined citations for this variant ...

Record last updated Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NM_000020.3(ACVRL1):c.631G>A (p.Gly211Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...