rs1060503248

Variant names:

• chr12-51916108-G-A
• rs1060503248
• NM_000020.3:c.1121G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-51916108-G-A
• chr12-51916108-G-C

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000020.3(ACVRL1):​c.1121G>A​(p.Arg374Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,480 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R374W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ACVRL1 NM_000020.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 9.99
• Publications: 16 publications found

Genes affected

ACVRL1 (HGNC:175): (activin A receptor like type 1) This gene encodes a type I cell-surface receptor for the TGF-beta superfamily of ligands. It shares with other type I receptors a high degree of similarity in serine-threonine kinase subdomains, a glycine- and serine-rich region (called the GS domain) preceding the kinase domain, and a short C-terminal tail. The encoded protein, sometimes termed ALK1, shares similar domain structures with other closely related ALK or activin receptor-like kinase proteins that form a subfamily of receptor serine/threonine kinases. Mutations in this gene are associated with hemorrhagic telangiectasia type 2, also known as Rendu-Osler-Weber syndrome 2. [provided by RefSeq, Jul 2008]

ACVRL1 Gene-Disease associations (from GenCC):

• telangiectasia, hereditary hemorrhagic, type 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp
• hereditary hemorrhagic telangiectasia

  Inheritance: AR, AD Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 21 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000020.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-51916107-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 8249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the ACVRL1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 203 curated pathogenic missense variants (we use a threshold of 10). The gene has 24 curated benign missense variants. Gene score misZ: 2.4458 (below the threshold of 3.09). Trascript score misZ: 3.182 (above the threshold of 3.09). GenCC associations: The gene is linked to telangiectasia, hereditary hemorrhagic, type 2, hereditary hemorrhagic telangiectasia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 12-51916108-G-A is Pathogenic according to our data. Variant chr12-51916108-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 411314.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000020.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACVRL1	NM_000020.3	MANE Select	c.1121G>A	p.Arg374Gln	missense	Exon 8 of 10	NP_000011.2
	ACVRL1	NM_001077401.2		c.1121G>A	p.Arg374Gln	missense	Exon 7 of 9	NP_001070869.1
	ACVRL1	NM_001406487.1		c.1121G>A	p.Arg374Gln	missense	Exon 9 of 11	NP_001393416.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACVRL1	ENST00000388922.9	TSL:1 MANE Select	c.1121G>A	p.Arg374Gln	missense	Exon 8 of 10	ENSP00000373574.4
	ACVRL1	ENST00000550683.5	TSL:1	c.1163G>A	p.Arg388Gln	missense	Exon 7 of 9	ENSP00000447884.1
	ACVRL1	ENST00000551576.6	TSL:1	c.1121G>A	p.Arg374Gln	missense	Exon 9 of 11	ENSP00000455848.2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251110 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461284 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726798

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111544

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152196 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74346

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.0000655 AC: 1 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 2 Pathogenic:6

Nov 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 374 of the ACVRL1 protein (p.Arg374Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with hereditary hemorrhagic telangiectasia (PMID: 12700602, 18285823, 21158752, 25970827). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 411314). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ACVRL1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ACVRL1 function (PMID: 20501893). This variant disrupts the p.Arg374 amino acid residue in ACVRL1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12700602, 15517393, 17384219, 20501893). 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.

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with hereditary hemorrhagic telangiectasia type 2 (MIM#600376). Protein truncating variants are known to cause disease through a loss of function mechanism, while missense variants have been associated with both loss of function and dominant negative mechanisms (PMIDs: 26176610, 16470589, 16282348). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Clinical expression is known to be extremely variable and age-dependent (PMID: 19767588). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated kinase domain (PMID: 20501893). (I) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. p.(Arg374Trp) has been reported in multiple families with hereditary hemorrhagic telangiectasia (HHT) and it is believed to have resulted from a founder effect (ClinVar; PMID: 33919892). In addition, p.(Arg374Gly) has been reported in an individual with HHT (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals with hereditary hemorrhagic telangiectasia and it is also believed to have resulted from a founder effect (ClinVar; PMID: 33919892). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Mutagenesis studies demonstrated that both p.(Arg374Gln) and p.(Arg374Trp) did not bind to the specific ligand BMP9 (PMID: 20501893). (SP) 1208 -Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Mar 30, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change is predicted to replace arginine with glutamine at codon 374 of the ACVRL1 protein (p.(Arg374Gln)). The arginine residue is evolutionarily conserved (100 vertebrates, UCSC), and is located in the protein kinase domain. There is a small physicochemical difference between arginine and glutamine. The variant is present in a single individual in a large population cohort (1/251,110 alleles in gnomAD v2.1). It is a recurrent variant that has been identified in multiple individuals with a clinical diagnosis of hereditary haemorrhagic telangiectasia (HHT), and segregates with disease in multiple families (PMID: 12700602, 12843319, 15517393, 17384219, 18673552, 18285823, 23919827, 25970827, 31511490). The variant alters the BMP9 response and reduces kinase activity in functional studies (PMID: 14684682, 20501893, 27869117). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). Two missense changes involving the same residue (p.Arg374Gly, p.Arg374Trp), but a larger physicochemical change, have been reported as pathogenic in HHT individuals (ClinVar). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as PATHOGENIC. Following criteria are met: PS4, PP1_Strong, PS3_Supporting, PM2_Supporting, PP3.

Jun 26, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ACVRL1 c.1121G>A; p.Arg374Gln variant (rs1060503248) has been reported in the literature in individuals with hereditary hemorrhagic telangiectasia (HHT) or pulmonary arterial hypertension (PAH) (Abdalla 2003, Harrison 2003, McDonald 2011, Yang 2018), and has been shown to have defective BMP9 ligand signaling (Ricard 2010). This variant has been reported in ClinVar (Variation ID: 411314) and is absent from the general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 374 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.654). Another amino acid substitution at this codon (p.Arg374Trp) has been reported in multiple individuals with HHT and is considered disease-causing (Harrison 2003, Nishida 2012). Based on available information, the p.Arg374Gln variant is considered to be pathogenic. REFERENCES Abdalla SA et al. Disease-associated mutations in conserved residues of ALK-1 kinase domain. Eur J Hum Genet. 2003 Apr;11(4):279-87. Harrison RE et al. Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia. J Med Genet. 2003 Dec;40(12):865-71. McDonald J et al. Molecular diagnosis in hereditary hemorrhagic telangiectasia: findings in a series tested simultaneously by sequencing and deletion/duplication analysis. Clin Genet. 2011 Apr;79(4):335-44. Nishida T et al. Brain arteriovenous malformations associated with hereditary hemorrhagic telangiectasia: gene-phenotype correlations. Am J Med Genet A. 2012 ; 158A(11): 2829-2834. Ricard N et al. Functional analysis of the BMP9 response of ALK1 mutants from HHT2 patients: a diagnostic tool for novel ACVRL1 mutations. Blood. 2010 Sep 2;116(9):1604-12. Yang H et al. Genetic analyses in a cohort of 191 pulmonary arterial hypertension patients. Respir Res. 2018 May 9;19(1):87.

Aug 14, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000%). Predicted Consequence/Location: Missense variant Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product (PMID: 20501893). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.65 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.97 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000411314 /PMID: 12700602). Different missense changes at the same codon (p.Arg374Gly, p.Arg374Trp) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000008249, VCV000946842 /PMID: 9245985). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Mar 20, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:3

Sep 12, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_strong, PM2, PM5, PS3, PS4

Jan 25, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies in transfected cultured cells suggest that although ACVRL1 receptors harboring R374Q can bind BMP9 ligand at the cell surface, the BMP9 signaling response is impaired (PMID: 20501893); Segregates with HHT in at least two affected relatives from two families (PMID: 12700602, 23919827); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18673552, 17384219, 23919827, 18285823, 14684682, 15517393, 17786384, 25970827, 21158752, 29743074, 26387786, 31511490, 34872578, 12700602, 32300199, 33919892, 20501893)

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACVRL1: PS4, PM1, PM5, PP1, PS3:Supporting

Pulmonary arterial hypertension related to hereditary hemorrhagic telangiectasia Pathogenic:1

Rare Disease Genomics Group, St George's University of London

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Cardiovascular phenotype Pathogenic:1

Nov 24, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R374Q pathogenic mutation (also known as c.1121G>A), located in coding exon 7 of the ACVRL1 gene, results from a G to A substitution at nucleotide position 1121. The arginine at codon 374 is replaced by glutamine, an amino acid with highly similar properties. This mutation was initially reported in in two possibly related hereditary hemorrhagic telangiectasia (HHT) families and was observed to segregate with disease in both families (Abdalla SA et al. Eur J Hum Genet, 2003 Apr;11:279-87). This mutation has been reported in additional individuals and families with HHT (Fontalba A et al. BMC Med. Genet., 2008 Aug;9:75; Chen YJ et al. Eur J Clin Invest, 2013 Oct;43:1016-24; McDonald J et al. Genet Med, 2020 07;22:1201-1205). The p.R374Q mutation is located in the intracellular kinase domain of the ALK1 protein, and in vitro functional studies showed this mutation had no functional activity in response to BMP9, a ligand for ALK1 (Ricard N et al. Blood, 2010 Sep;116:1604-12). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	-0.044	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		10
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.95		Loss of methylation at R374 (P = 0.0273)
MVP		0.93
MPC		1.7
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.95
gMVP		0.90
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1060503248; hg19: chr12-52309892; COSMIC: COSV66359673; COSMIC: COSV66359673;