Submissions for variant NM_000020.3(ACVRL1):c.698C>T (p.Ser233Leu)

dbSNP: rs762773076

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000508251	SCV000602424	pathogenic	not specified	2016-11-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001069361	SCV001234525	pathogenic	Telangiectasia, hereditary hemorrhagic, type 2	2024-08-06	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 233 of the ACVRL1 protein (p.Ser233Leu). This variant is present in population databases (rs762773076, gnomAD 0.0009%). This missense change has been observed in individual(s) with hereditary hemorrhagic telangiectasia (PMID: 16525724, 19767588, 21158752; Invitae). ClinVar contains an entry for this variant (Variation ID: 439385). 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%. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV002292558	SCV002585396	likely pathogenic	not provided	2022-08-01	criteria provided, single submitter	clinical testing	ACVRL1: PM1, PM2, PP4, PS4:Supporting
Ambry Genetics	RCV002367696	SCV002664440	uncertain significance	Cardiovascular phenotype	2022-01-06	criteria provided, single submitter	clinical testing	The p.S233L variant (also known as c.698C>T), located in coding exon 5 of the ACVRL1 gene, results from a C to T substitution at nucleotide position 698. The serine at codon 233 is replaced by leucine, an amino acid with dissimilar properties. This variant was identified in an individual with epistaxis, telangiectasias, pulmonary arteriovenous malformations, and a family history (Argyriou L et al. Int. J. Mol. Med., 2006 Apr;17:655-9). It was also identified in an individual meeting clinical criteria for hereditary hemorrhagic telangiectasia in conjunction with the ENG p.P198L alteration (McDonald J et al. J Mol Diagn, 2009 Nov;11:569-75; McDonald J et al. Clin. Genet., 2011 Apr;79:335-44). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, the clinical significance of this alteration remains unclear.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001069361	SCV002769541	likely pathogenic	Telangiectasia, hereditary hemorrhagic, type 2	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as likely 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 haemorrhagic telangiectasia type 2 (MIM# 600376) (PMID: 16282348; 26176610). (I) 0115 - Variants in this gene are known to have variable expressivity. Clinical expression is extremely variable and age dependent (PMID: 19767588). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to leucine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated protein kinase domain (Uniprot). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has previously been reported in individuals with hereditary haemorrhagic telangiectasia (ClinVar, PMID: 16525724, PMID: 19767588, PMID: 21158752). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Mayo Clinic Laboratories, Mayo Clinic	RCV002292558	SCV004226862	likely pathogenic	not provided	2023-04-28	criteria provided, single submitter	clinical testing	PP1, PP4, PM2_supporting, PS4