ClinVar Miner

Submissions for variant NM_000487.6(ARSA):c.248T>C (p.Leu83Pro)

gnomAD frequency: 0.00001  dbSNP: rs1190061000
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Mayo Clinic Laboratories, Mayo Clinic RCV002247162 SCV002520074 likely pathogenic not provided 2021-12-21 criteria provided, single submitter clinical testing PP3, PP4, PM2, PM3
Labcorp Genetics (formerly Invitae), Labcorp RCV003500692 SCV004300076 likely pathogenic Metachromatic leukodystrophy 2024-11-15 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 83 of the ARSA protein (p.Leu83Pro). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 24001781). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as Leu81Pro. ClinVar contains an entry for this variant (Variation ID: 1686649). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ARSA protein function with a positive predictive value of 95%. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004526919 SCV005039703 uncertain significance not specified 2024-03-19 criteria provided, single submitter clinical testing Variant summary: ARSA c.248T>C (p.Leu83Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.3e-06 in 230062 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.248T>C has been reported in the literature in individuals affected with Metachromatic Leukodystrophy (Luzi_2013). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 24001781). ClinVar contains an entry for this variant (Variation ID: 1686649). Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics RCV003500692 SCV005656826 likely pathogenic Metachromatic leukodystrophy 2024-03-18 criteria provided, single submitter clinical testing

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