Submissions for variant NM_000020.3(ACVRL1):c.500C>G (p.Ser167Cys)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, ClinGen	RCV003096562	SCV004805889	uncertain significance	Telangiectasia, hereditary hemorrhagic, type 2	2024-03-15	reviewed by expert panel	curation	The NM_000020.3: c.500C>G variant in ACVRL1 is a missense variant predicted to cause substitution of serine by cysteine at amino acid 167 (p.Ser167Cys). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in a proband with a phenotype consistent of HHT (PS4_Supporting; PMID: 32300199, Internal lab contributors). The computational splicing predictor SpliceAI gives a score of 0.84 for donor loss, predicting that the variant disrupts the donor splice site of intron 4 of ACVRL1 (PP3). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PM2_Supporting, PS4_Supporting, PP3 (specification version 1.0.0; 1/4/2024).
Ambry Genetics	RCV002343094	SCV002644538	uncertain significance	Cardiovascular phenotype	2018-02-28	criteria provided, single submitter	clinical testing	The p.S167C variant (also known as c.500C>G), located in coding exon 3 of the ACVRL1 gene, results from a C to G substitution at nucleotide position 500. The serine at codon 167 is replaced by cysteine, an amino acid with dissimilar properties. This variant was identified in one individual with a clinical diagnosis of hererditary hemorrhagic telangiectasia (Gedge F et al. J Mol Diagn, 2007 Apr;9:258-65). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on available evidence to date, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003096562	SCV003496254	likely pathogenic	Telangiectasia, hereditary hemorrhagic, type 2	2022-09-19	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 167 of the ACVRL1 protein (p.Ser167Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary hemorrhagic telangiectasia (PMID: 32300199; Invitae). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.