ClinVar Miner

Submissions for variant NM_000487.6(ARSA):c.1283C>T (p.Pro428Leu) (rs28940893)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000392246 SCV000110801 pathogenic not provided 2015-08-06 criteria provided, single submitter clinical testing
GeneDx RCV000392246 SCV000329084 pathogenic not provided 2018-11-28 criteria provided, single submitter clinical testing The P428L variant is a common variant inthe ARSA gene, accounting for approximately 12% of pathogenic alleles, and has been associated withjuvenile- and adult-onset metachromatic leukodystrophy (Gieselmann et al., 1994; Biffi et al., 2008;Cesani et al., 2015). Functional studies found that P428L is associated with significantly reducedenzyme activity (Polten et al., 1991). In summary, we interpret P428L as a pathogenic variant
Genetic Services Laboratory, University of Chicago RCV000020314 SCV000593419 pathogenic Metachromatic leukodystrophy 2016-02-11 criteria provided, single submitter clinical testing
Invitae RCV000020314 SCV000627138 pathogenic Metachromatic leukodystrophy 2018-12-11 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 428 of the ARSA protein (p.Pro428Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs28940893, ExAC 0.06%). This variant has been reported in the literature as homozygous or in combination with other rare ARSA variants in individuals affected with metachromatic leukodystrophy (MLD) (PMID: 11941485, 26462614, 9096767, 9090526, 1670590). This variant is also known in the literature as p.Pro426Leu. ClinVar contains an entry for this variant (Variation ID: 3052). Experimental studies have shown that this missense change causes a deficiency in ARSA protein octamerization, lack of stability in lysosomes and reduced enzymatic activity (PMID: 11941485, 11777924). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000020314 SCV000678014 pathogenic Metachromatic leukodystrophy 2015-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000020314 SCV000696807 pathogenic Metachromatic leukodystrophy 2019-03-10 criteria provided, single submitter clinical testing Variant summary: ARSA c.1283C>T (p.Pro428Leu) 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 0.0004 in 268786 control chromosomes. c.1283C>T has been reported in the literature in multiple individuals affected with Metachromatic Leukodystrophy (Polten_1991, Barth_1993). These data indicate that the variant is very likely to be associated with disease. A functional study, Polten_1991, found the enzymatic activity to be <10% of normal activity. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000020314 SCV000893596 pathogenic Metachromatic leukodystrophy 2018-10-31 criteria provided, single submitter clinical testing
OMIM RCV000003195 SCV000023353 pathogenic Metachromatic leukodystrophy, juvenile type 1997-01-01 no assertion criteria provided literature only
OMIM RCV000003196 SCV000023354 pathogenic Arylsulfatase a, allele a 1997-01-01 no assertion criteria provided literature only
OMIM RCV000003197 SCV000023355 pathogenic Metachromatic leukodystrophy, adult type 1997-01-01 no assertion criteria provided literature only
GeneReviews RCV000020314 SCV000040689 pathologic Metachromatic leukodystrophy 2011-08-25 no assertion criteria provided curation Converted during submission to Pathogenic.

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