ClinVar Miner

Submissions for variant NM_000487.6(ARSA):c.418C>G (p.His140Asp)

dbSNP: rs199476358
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Total submissions: 5
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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, LabCorp 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, Revvity RCV000667286 SCV003817273 likely pathogenic Metachromatic leukodystrophy 2022-07-07 criteria provided, single submitter clinical testing
UniProtKB/Swiss-Prot RCV000058963 SCV000090484 not provided not provided no assertion provided not provided

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