Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Eurofins Ntd Llc |
RCV000152793 | SCV000202183 | uncertain significance | not provided | 2016-10-27 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001582624 | SCV001821303 | uncertain significance | not specified | 2021-08-19 | criteria provided, single submitter | clinical testing | Variant summary: ARSA c.465G>A (p.Gln155Gln) alters a conserved nucleotide located as the last nucleotide of exon 2 adjacent to the intronic canonical splice donor site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a canonical 5' splice donor site. One predicts the variant abolishes a canonical 5' splicing donor site. However, these predictions have yet to be confirmed by traceable functional studies. The variant was absent in 240440 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.465G>A has been reported in the literature as a non-informative genotype in at-least one individual affected with Metachromatic Leukodystrophy, who reportedly harbored this variant (inherited from the father) along with a deletion on the other allele (Chen_2018). Based on RNA analysis, this variant was reported to impact splicing and reported as having a translational impact resulting in p.Lys125ProfsX17. However, primary evidence supporting this conclusion was not provided in this report. Neither was the identity of the exact deletion on the other allele unequivocally specified. Therefore, in our ascertainment, this report does not provide unequivocal conclusions about association of the variant with Metachromatic Leukodystrophy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Invitae | RCV001850084 | SCV002264811 | likely pathogenic | Metachromatic leukodystrophy | 2024-01-25 | criteria provided, single submitter | clinical testing | This sequence change affects codon 155 of the ARSA mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ARSA protein. This variant also falls at the last nucleotide of exon 2, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with metachromatic leukodystrophy (PMID: 30057904). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 166691). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. |