Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Counsyl | RCV000667286 | SCV000791714 | uncertain significance | Metachromatic leukodystrophy | 2017-05-26 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000667286 | SCV001401371 | pathogenic | Metachromatic leukodystrophy | 2023-04-07 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ARSA function (PMID: 19606494). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ARSA protein function. ClinVar contains an entry for this variant (Variation ID: 68132). This variant is also known as c.412C>G (His138Asp) in literature. This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 18786133, 33855715; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs199476358, gnomAD 0.003%). This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 140 of the ARSA protein (p.His140Asp). |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000667286 | SCV001983480 | likely pathogenic | Metachromatic leukodystrophy | 2021-09-15 | criteria provided, single submitter | clinical testing | Variant summary: ARSA c.418C>G (p.His140Asp) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain (IPR000917) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.3e-05 in 238808 control chromosomes (gnomAD). c.418C>G has been reported in the literature in at least one individual affected with Metachromatic Leukodystrophy (Biffi_2008). Experimental evidence evaluating an impact on protein function demonstrated the variant results in low residual enzyme activity (Cesani_2009). One ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic and another ClinVar submitter (evaluation after 2014) cites it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
Revvity Omics, |
RCV000667286 | SCV003817273 | likely pathogenic | Metachromatic leukodystrophy | 2022-07-07 | criteria provided, single submitter | clinical testing | |
Uni |
RCV000058963 | SCV000090484 | not provided | not provided | no assertion provided | not provided |