rs863223413

Positions:

• chr12-51915450-G-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PS3_Supporting PP4_Moderate PP3 PM2_Supporting PS4 PP1_Strong PM1

This summary comes from the ClinGen Evidence Repository: The NM_000020.3: c.998G>T variant in ACVRL1 is a missense variant predicted to cause substitution of serine by isoleucine at amino acid 333 (p.Ser333Ile). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in >4 probands with a phenotype consistent of HHT (PS4; Internal lab contributors). At least one patient's phenotype meets Curacao Criteria for HHT, and sequencing and large deletion/duplication analysis was performed for ENG and ACVRL1, which is highly specific for HHT (PP4_Moderate; Internal lab contributors). The variant has been reported to segregate with disease in a large HHT family (PP1_Strong; Internal lab contributors). This variant resides within a region, Arg329-Asn335 (catalytic loop), of ACVRL1 that is defined as a critical functional domain/residue by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel (PM1). The computational predictor REVEL gives a score of 0.975, which is above the threshold of ≥0.644, evidence that correlates with impact to ACVRL1 function (PP3). Additionally, western blot in HEK293T, COS7 and Hep3B mutant cells showed reduced surface expression of the variant protein and dominant-negative effect. Moreover, the variant induces embryonic dorsalization indicating that this variant impacts protein function (PS3_Supporting; PMID:16282348). In summary, this variant meets the criteria to be classified as pathogenic for Hereditary Hemorrhagic Telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PM1, PM2_Supporting, PS4, PS3_Supporting, PP1_Strong, PP3, PP4_Moderate (specification version 1.0.0; 1/04/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA322708/MONDO:0010880/135

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACVRL1 NM_000020.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:8
• 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 15 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACVRL1	NM_000020.3	c.998G>T	p.Ser333Ile	missense_variant	7/10	ENST00000388922.9	NP_000011.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACVRL1	ENST00000388922.9	c.998G>T	p.Ser333Ile	missense_variant	7/10	1	NM_000020.3	ENSP00000373574.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 2 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 04, 2023	This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 333 of the ACVRL1 protein (p.Ser333Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary hemmorhagic telangiectasia (PMID: 9245985, 10767348, 12843319, 21158752). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 212802). 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: 16282348). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, reviewed by expert panel	curation	ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, ClinGen	Mar 15, 2024	The NM_000020.3: c.998G>T variant in ACVRL1 is a missense variant predicted to cause substitution of serine by isoleucine at amino acid 333 (p.Ser333Ile). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in >4 probands with a phenotype consistent of HHT (PS4; Internal lab contributors). At least one patient's phenotype meets Curacao Criteria for HHT, and sequencing and large deletion/duplication analysis was performed for ENG and ACVRL1, which is highly specific for HHT (PP4_Moderate; Internal lab contributors). The variant has been reported to segregate with disease in a large HHT family (PP1_Strong; Internal lab contributors). This variant resides within a region, Arg329-Asn335 (catalytic loop), of ACVRL1 that is defined as a critical functional domain/residue by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel (PM1). The computational predictor REVEL gives a score of 0.975, which is above the threshold of greater than or equal to 0.644, evidence that correlates with impact to ACVRL1 function (PP3). Additionally, western blot in HEK293T, COS7 and Hep3B mutant cells showed reduced surface expression of the variant protein and dominant-negative effect. Moreover, the variant induces embryonic dorsalization indicating that this variant impacts protein function (PS3_Supporting; PMID: 16282348). In summary, this variant meets the criteria to be classified as pathogenic for Hereditary Hemorrhagic Telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PM1, PM2_Supporting, PS4, PS3_Supporting, PP1_Strong, PP3, PP4_Moderate (specification version 1.0.0; 1/04/2024). -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 07, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 04, 2023	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; Published functional studies in HeLa cells showed intracellular localization and co-localized to the endoplasmic reticulum as opposed to wild-type, and the variant appears to function as a trafficking defect (Harrison et al., 2003; Gu et al., 2006).; This variant is associated with the following publications: (PMID: 10767348, 29398197, 9245985, 15266205, 12843319, 23805858, 32300199, 16282348, 12700602, 29483005, 21158752, 14684682, 10946360) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 01, 2022	PP1_strong, PP3, PP4, PM2_supporting, PS3_moderate, PS4 -

Hereditary hemorrhagic telangiectasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 07, 2024

Variant summary: ACVRL1 c.998G>T (p.Ser333Ile) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249936 control chromosomes. c.998G>T has been reported in the literature in multiple individuals affected with Hereditary Hemorrhagic Telangiectasia (examples: Abdalla_2003 and McDonald_2011). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 12700602, 21158752). ClinVar contains an entry for this variant (Variation ID: 212802). Based on the evidence outlined above, the variant was classified as pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 10, 2017

The p.S333I pathogenic mutation (also known as c.998G>T), located in coding exon 6 of the ACVRL1 gene, results from a G to T substitution at nucleotide position 998. The serine at codon 333 is replaced by isoleucine, an amino acid with dissimilar properties. This mutation has been identified in several individuals with HHT, including multiple affected generations of a large family (Berg JN et al. Am. J. Hum. Genet., 1997 Jul;61:60-7; McDonald JE et al. Am. J. Med. Genet., 2000 Aug;93:320-7; Lux A et al. Orphanet J Rare Dis, 2013 Jun;8:94). Functional studies demonstrated this mutation had a dominant-negative effect on the normal protein and resulted in reduced protein expression on the cell surface (Gu Y et al. Blood, 2006 Mar;107:1951-4). 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	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;.;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M;.;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.4	D;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.98
MutPred		0.97		Loss of disorder (P = 0.0373);.;.;
MVP		0.99
MPC		1.7
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.99
gMVP		0.94

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: rs863223413; hg19: chr12-52309234;