rs1131691686

chr12-51916122-G-Achr12-51916122-G-C

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000020.3(ACVRL1):c.1135G>A(p.Glu379Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,612 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E379A) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ACVRL1 NM_000020.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 9.99

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]

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 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 chr12-51916123-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1729692.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, ACVRL1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.996
• PP5: Variant 12-51916122-G-A is Pathogenic according to our data. Variant chr12-51916122-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 429940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-51916122-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACVRL1	NM_000020.3	c.1135G>A	p.Glu379Lys	missense_variant	8/10	ENST00000388922.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACVRL1	ENST00000388922.9	c.1135G>A	p.Glu379Lys	missense_variant	8/10	1	NM_000020.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251236 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135802

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 SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461612 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727060

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 2 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jul 18, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2023	The ACVRL1 c.1135G>A; p.Glu379Lys variant (rs1131691686) has been reported in multiple unrelated individuals diagnosed with hereditary hemorrhagic telangiectasia (Brakensiek 2008, Fontalba 2008, Kuehl 2005, Lenato 2006, Lesca 2004, Nishida 2012). In functional assays, this variant exhibits a decreased BMP9 response and inability to properly localize to the cell surface (Alaa El Din 2015). This variant is reported in the ClinVar database (Variation ID: 429940), and it is found on only two chromosomes (2/251236 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism. The glutamic acid at codon 379 is a highly conserved residue in the protein kinase domain, computational analyses predict that this variant is deleterious (REVEL: 0.969). Based on the above information, this variant is considered pathogenic. References: Alaa El Din F et al. Functional and splicing defect analysis of 23 ACVRL1 mutations in a cohort of patients affected by Hereditary Hemorrhagic Telangiectasia. PLoS One. 2015 Jul 15;10(7):e0132111. Brakensiek K et al. Detection of a significant association between mutations in the ACVRL1 gene and hepatic involvement in German patients with hereditary haemorrhagic telangiectasia. Clin Genet. 2008 Aug;74(2):171-7. Fontalba A et al. Mutation study of Spanish patients with hereditary hemorrhagic telangiectasia. BMC Med Genet. 2008 Aug 1;9:75. Kuehl HK et al. Hepatic manifestation is associated with ALK1 in hereditary hemorrhagic telangiectasia: identification of five novel ALK1 and one novel ENG mutations. Hum Mutat. 2005 Mar;25(3):320. Lenato GM et al. DHPLC-based mutation analysis of ENG and ALK-1 genes in HHT Italian population. Hum Mutat. 2006 Feb;27(2):213-4. Lesca G et al. Molecular screening of ALK1/ACVRL1 and ENG genes in hereditary hemorrhagic telangiectasia in France. Hum Mutat. 2004 Apr;23(4):289-99. Nishida T et al. Brain arteriovenous malformations associated with hereditary hemorrhagic telangiectasia: gene-phenotype correlations. Am J Med Genet A. 2012 Nov;158A(11):2829-34. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 379 of the ACVRL1 protein (p.Glu379Lys). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individuals with hereditary hemorrhagic telangiectasia (PMID: 15024723, 15712270, 16429404, 18498373, 22991266, 24603890). ClinVar contains an entry for this variant (Variation ID: 429940). 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%. Experimental studies have shown that this missense change affects ACVRL1 function (PMID: 26176610). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 22, 2023	PP3, PM2_supporting, PS3, PS4 -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 20, 2016	The E379K variant has been reported in multiple unrelated individuals from various ethnic backgrounds who have been diagnosed with HHT (Lesca et al., 2004; Brusgaard et al., 2004; Kuehl et al., 2005; Lenato et al., 2006; Brakensiek et al., 2008; Fontalba et al., 2008; Nishida et al., 2012). Considering all publications, the E379K variant was not observed in 576 control alleles (Lesca et al., 2004; Lenato et al., 2006). In addition, the E379K variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E379K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Furthermore, functional studies using the BMP9 response assay and Western blot analysis confirm that E379K has a negative impact on ACVRL1 receptor activity and protein maturation (El Din et al., 2015). A missense variant in the same residue (E379D) has been reported in the Human Gene Mutation Database in association with HHT (Stenson et al., 2014); however, the pathogenicity of this variant has not been definitively determined. Finally, despite the fact that several publications describe an association between the E379K variant in the ACVRL1 gene and HHT, family history information and segregation data was not provided. -

Hereditary hemorrhagic telangiectasia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 12, 2024

The p.Glu379Lys variant in ACVRL1 has been reported in >5 individuals with hereditary hemorrhagic telangiectasia (HHT; Lesca 2004 PMID: 15024723, Kuehl 2005 PMID: 15712270, Lenato 2006 PMID: 16429404). It has also been identified in 0.001% (1/69794) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID 429940). Computational prediction tools and conservation analyses support that this variant may impact the protein. In vitro functional studies provide some evidence that this variant impacts protein function (Alaa El Din 2015 PMID: 26176610); however, these types of assays may not accurately represent biological function. Additionally, the number of ACVRL1 missense variants in the general population is lower than expected (Z=3.18, https://gnomad.broadinstitute.org/gene/ENSG00000139567), providing some evidence that this variant may not be tolerated. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HHT. ACMG/AMP Criteria applied: PS4, PP2, PP3, PM2_supporting, PS3_supporting. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 27, 2021

The p.E379K pathogenic mutation (also known as c.1135G>A), located in coding exon 7 of the ACVRL1 gene, results from a G to A substitution at nucleotide position 1135. The glutamic acid at codon 379 is replaced by lysine, an amino acid with similar properties. This mutation has been reported in several individuals with hereditary hemorrhagic telangiectasia (HHT) from multiple research groups. The first report of p.E379K was in a French individual with a probable diagnosis of HHT (Lesca G et al. Hum. Mutat., 2004 Apr;23:289-99). This mutation was also reported in three unrelated Italian individuals meeting Curacao diagnostic criteria. Familial co-segregation of p.E379K and HHT was reportedly observed in two of the three aforementioned individuals (Lenato GM et al. Hum. Mutat., 2006 Feb;27:213-4). More recently, this mutation was reported in two individuals with a clinical diagnosis of HHT by Curacao diagnostic criteria (Zhao Y et al. Mol Genet Genomic Med, 2019 09;7:e893). In a separate study, this mutation has also been reported in a pulmonary arterial hypertension (PAH) cohort (Wang XJ et al. Eur Respir J, 2019 03;53:). In addition, in vitro functional studies demonstrated that the resulting protein is predominantly immature and not localized to the cell surface (Alaa El Din F et al. PLoS ONE, 2015 Jul;10:e0132111). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.61
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D;.;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	1.0	D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	4.5	H;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-4.0	D;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.99
MutPred		0.97		Gain of methylation at E379 (P = 0.0068);.;.;
MVP		0.99
MPC		1.6
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.99
gMVP		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs1131691686; hg19: chr12-52309906;