Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001238944 | SCV001411781 | uncertain significance | Metachromatic leukodystrophy | 2022-11-29 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 140 of the ARSA protein (p.His140Leu). This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.His140 amino acid residue in ARSA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18786133, 19606494; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 964677). This variant has not been reported in the literature in individuals affected with ARSA-related conditions. |
| Neuberg Supratech Reference Laboratories Pvt Ltd, |
RCV001238944 | SCV002073108 | uncertain significance | Metachromatic leukodystrophy | criteria provided, single submitter | clinical testing | The missense variant p.H140L in ARSA (NM_000487.6) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.H140L variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. 2 variants within 6 amino acid positions of the variant p.H140L have been shown to be pathogenic, while none have been shown to be benign. The p.H140L missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.419 in ARSA is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. |