Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
3billion | RCV002283451 | SCV002573006 | likely pathogenic | Metachromatic leukodystrophy | 2022-09-01 | criteria provided, single submitter | clinical testing | The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.86; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with ARSA -related disorder (PMID: 18693274). A different missense change at the same codon (p.Asn284Lys) has been reported to be associated with ARSA -related disorder (ClinVar ID: VCV000431089 / PMID: 28762252). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. |
Invitae | RCV002283451 | SCV004300068 | pathogenic | Metachromatic leukodystrophy | 2023-11-02 | criteria provided, single submitter | clinical testing | This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 284 of the ARSA protein (p.Asn284Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 33185815). This variant is also known as c.845A>G (p.Asn282Ser). ClinVar contains an entry for this variant (Variation ID: 68152). 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 ARSA protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ARSA function (PMID: 18693274). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. |
Uni |
RCV000058983 | SCV000090504 | not provided | not provided | no assertion provided | not provided |