rs1085307409

Variant names:

• chr12-51915270-T-C
• rs1085307409
• NM_000020.3:c.818T>C

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000020.3(ACVRL1):​c.818T>C​(p.Leu273Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar 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:5
• Conservation: PhyloP100: 8.01

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 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 hereditary hemorrhagic telangiectasia, telangiectasia, hereditary hemorrhagic, type 2.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 12-51915270-T-C is Pathogenic according to our data. Variant chr12-51915270-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 426017.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-51915270-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACVRL1	NM_000020.3	c.818T>C	p.Leu273Pro	missense_variant	Exon 7 of 10	ENST00000388922.9	NP_000011.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACVRL1	ENST00000388922.9	c.818T>C	p.Leu273Pro	missense_variant	Exon 7 of 10	1	NM_000020.3	ENSP00000373574.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461834 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727212

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 2 Pathogenic:2

Jan 30, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ACVRL1 c.818T>C; p.Leu273Pro variant (rs1085307409) is reported in the literature in individuals with suspected HHT and shown to segregate with disease in affected family members (Abdalla 2005, Kitonyi 2008, Machado 2015, Smoot 2009, Westermann 2011). This variant is also reported in ClinVar (Variation ID: 426017). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.776). Based on available information, this variant is considered to be pathogenic. References: Abdalla SA et al. Novel mutations and polymorphisms in genes causing hereditary hemorrhagic telangiectasia. Hum Mutat. 2005 Mar;25(3):320-1. PMID: 15712271. Kitonyi GW et al. Hereditary haemorrhagic telangiectasia in a black adult male: case report. East Afr Med J. 2008 Aug;85(8):412-6. PMID: 19115559. Machado RD et al. Pulmonary Arterial Hypertension: A Current Perspective on Established and Emerging Molecular Genetic Defects. Hum Mutat. 2015 Dec;36(12):1113-27. PMID: 26387786. Smoot LB et al. Clinical features of pulmonary arterial hypertension in young people with an ALK1 mutation and hereditary haemorrhagic telangiectasia. Arch Dis Child. 2009 Jul;94(7):506-11. PMID: 19357124. Westermann CJ et al. Is hereditary haemorrhagic telangiectasia rare in the black race? The first sub-Saharan mutation. Haemophilia. 2011 Jan;17(1):e244. PMID: 20609011. -

May 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 273 of the ACVRL1 protein (p.Leu273Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of hereditary hemorrhagic telangiectasia (PMID: 15712271). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 426017). 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%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

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

- -

Hereditary hemorrhagic telangiectasia Pathogenic:1

Dec 09, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Leu273Pro variant in ACVRL1 has been reported in 3 individuals with Hereditary Hemorrhagic Telangiectasia (HHT) and segregated with disease in 7 affected relatives from 2 families (Abdalla 2005, Smoot 2009, Westerman 2011). It was absent from large population studies. Computational prediction tools and conservation analysis suggest that the p.Leu273Pro variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets our criteria to be classified as pathogenic for hereditary hemorrhagic telangiectasia in an autosomal dominant manner (http://www.partners.org/personalizedmedicine/LMM) based upon segregation studies. -

Cardiovascular phenotype Pathogenic:1

Jul 15, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L273P pathogenic mutation (also known as c.818T>C), located in coding exon 6 of the ACVRL1 gene, results from a T to C substitution at nucleotide position 818. The leucine at codon 273 is replaced by proline, an amino acid with similar properties. This mutation was described in a child with pulmonary arteriovenous malformation (PAVM) and was found to track with disease in the affected mother, grandmother, and maternal aunt (Abdalla SA et al. Hum. Mutat., 2005 Mar;25:320-1). In another study, this mutation was also described in a child presenting with pulmonary arterial hypertension and a PAVM; the mutation also tracked in clinically affected family members (Smoot LB et al. Arch. Dis. Child., 2009 Jul;94:506-11). This mutation was identified in a Kenyan male with epistaxis, telangiectasias, and a family history of epistaxis (Kitonyi GW et al. East Afr Med J, 2008 Aug;85:412-6; Westermann CJ et al. Haemophilia, 2011 Jan;17:e244). 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	1.0
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	D;.;D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Uncertain	0.058	D
MutationAssessor	Benign	2.0	M;.;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-6.8	D;D;D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.99
MutPred		0.96		Gain of disorder (P = 0.0157);.;.;
MVP		0.97
MPC		2.0
ClinPred		1.0	D
GERP RS		5.3
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: rs1085307409; hg19: chr12-52309054;