Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001042683 | SCV001206382 | pathogenic | Metachromatic leukodystrophy | 2020-12-24 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant disrupts mRNA splicing and is expected to lead to the loss of protein expression (PMID:14571263). This variant has been observed in individual(s) with metachromatic leukodystrophy (PMID: 14571263, 18786133). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.849-1G>A in the literature. This variant is present in population databases (rs754898479, ExAC 0.002%). This sequence change affects an acceptor splice site in intron 4 of the ARSA gene. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001042683 | SCV002598634 | pathogenic | Metachromatic leukodystrophy | 2022-09-26 | criteria provided, single submitter | clinical testing | Variant summary: ARSA c.855-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Regis_2004). The variant allele was found at a frequency of 8.1e-06 in 246424 control chromosomes. c.855-1G>A has been reported in the literature in individuals affected with Metachromatic Leukodystrophy (Regis_2004, Fumagalli_2021). These data indicate that the variant is associated with disease. One publication reports experimental evidence evaluating an impact on protein function, with the variant resulting in reduced enzyme activity. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, classifying the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Gelb Laboratory, |
RCV001042683 | SCV005046710 | not provided | Metachromatic leukodystrophy | no assertion provided | in vitro |