ClinVar Miner

Submissions for variant NM_000487.6(ARSA):c.413C>T (p.Pro138Leu)

dbSNP: rs74315462
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000675081 SCV000800583 uncertain significance Metachromatic leukodystrophy 2017-08-30 criteria provided, single submitter clinical testing
Invitae RCV000675081 SCV001592679 pathogenic Metachromatic leukodystrophy 2022-11-01 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 3064). This variant is also known as P136L. This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 7860068). This variant is present in population databases (rs74315462, gnomAD 0.006%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 138 of the ARSA protein (p.Pro138Leu). 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) performed at Invitae indicates that this missense variant is expected to disrupt ARSA protein function. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro138 amino acid residue in ARSA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22854541). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects ARSA function (PMID: 7860068).
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine RCV000675081 SCV002073107 pathogenic Metachromatic leukodystrophy criteria provided, single submitter clinical testing The missense variant p.P138L in ARSA (NM_000487.6) causes a change at the same amino acid residue as a previously established pathogenic variant. This variant has been observed to be homozygous in an individual affected with metachromatic leukodystrophy (Kafert S et al, 1995). This variant has been reported to affect ARSA protein function (Kafert S et al, 1995). The p.P138L variant is observed in 1/17,802 (0.0056%) alleles from individuals of East Asian background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000003210 SCV000023368 pathogenic Metachromatic leukodystrophy, severe 2018-11-07 no assertion criteria provided literature only

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