NM_000020.3(ACVRL1):c.140G>C (p.Arg47Pro) AND Telangiectasia, hereditary hemorrhagic, type 2

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 3, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV002272232.6

Allele description [Variation Report for NM_000020.3(ACVRL1):c.140G>C (p.Arg47Pro)]

NM_000020.3(ACVRL1):c.140G>C (p.Arg47Pro)

Gene:

ACVRL1:activin A receptor like type 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12q13.13

Genomic location:

Preferred name:

NM_000020.3(ACVRL1):c.140G>C (p.Arg47Pro)

HGVS:

NC_000012.12:g.51913177G>C
NG_009549.1:g.10760G>C
NM_000020.3:c.140G>CMANE SELECT
NM_001077401.2:c.140G>C
NP_000011.2:p.Arg47Pro
NP_000011.2:p.Arg47Pro
NP_001070869.1:p.Arg47Pro
LRG_543t1:c.140G>C
LRG_543:g.10760G>C
LRG_543p1:p.Arg47Pro
NC_000012.11:g.52306961G>C
NM_000020.2:c.140G>C

Protein change:

R47P

Links:

dbSNP: rs774389618

NCBI 1000 Genomes Browser:

rs774389618

Molecular consequence:

NM_000020.3:c.140G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001077401.2:c.140G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Telangiectasia, hereditary hemorrhagic, type 2 (HHT2)
Synonyms:: Telangiectasia, hereditary hemorrhagic, type II; Osler Weber Rendu syndrome type 2
Identifiers:: MONDO: MONDO:0010880; MedGen: C1838163; Orphanet: 774; OMIM: 600376

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002558028	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 25, 2020)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16470589, 16542389, 22991266, 26176610, 25741868
SCV003441097	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 3, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16470589, 16542389, 22991266, 26176610, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002558028

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 25, 2020)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV003441097

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 3, 2024)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Mutation study of Spanish patients with hereditary hemorrhagic telangiectasia and expression analysis of Endoglin and ALK1.

Fernandez-L A, Sanz-Rodriguez F, Zarrabeitia R, Perez-Molino A, Morales C, Restrepo CM, Ramirez JR, Coto E, Lenato GM, Bernabeu C, Botella LM.

Hum Mutat. 2006 Mar;27(3):295.

PubMed [citation]

PMID:: 16470589

See all PubMed Citations (6)

Details of each submission

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002558028.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0104 - Dominant Negative is a mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from arginine to proline (exon 3). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0309 - Alternative amino acid changes at the same position have been observed in gnomAD (5 heterozygotes, 0 homozygotes). (N) 0502 - Missense variant with conflicting in-silico predictions and/or uninformative conservation. (N) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0802 - Moderate previous evidence of pathogenicity in unrelated individuals. The variant has previously been described as pathogenic in patients with hereditary haemorrhagic telangiectasia (PMID: 16542389, 16470589, 22991266, 26176610), however it has also been classified as a VUS (ClinVar). (P) 0902 - Moderate evidence for segregation with disease. The variant has been shown to segregate with disease in six affected individuals from one family (PMID: 16470589). (P) 1002 - Moderate functional evidence supporting abnormal protein function. Functional studies in transfected cells showed that the variant resulted in a non-functional protein (PMID: 26176610). (P) 1101 - Very strong and specific phenotype match. (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003441097.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 47 of the ACVRL1 protein (p.Arg47Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary hemorrhagic telangiectasia (PMID: 16470589, 16542389, 22991266, 26176610). ClinVar contains an entry for this variant (Variation ID: 381525). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ACVRL1 protein function. Experimental studies have shown that this missense change affects ACVRL1 function (PMID: 26176610). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

ClinVar

Relating variation to medicine