ClinVar Miner

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

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Total submissions: 18
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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 2020-10-07 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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
Baylor Genetics RCV000020314 SCV001163453 pathogenic Metachromatic leukodystrophy criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000020314 SCV001193818 pathogenic Metachromatic leukodystrophy 2019-11-12 criteria provided, single submitter clinical testing NM_000487.5(ARSA):c.1283C>T(P428L) is classified as pathogenic in the context of metachromatic leukodystrophy. Please note that the P428L variant is associated with the juvenile or adult form of this disease. Sources cited for classification include the following: PMID 8095918, 20339381, 11777924 and 1670590. Classification of NM_000487.5(ARSA):c.1283C>T(P428L) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000392246 SCV001245875 pathogenic not provided 2018-09-01 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000020314 SCV001429405 pathogenic Metachromatic leukodystrophy 2019-01-30 criteria provided, single submitter clinical testing This variant was identified as homozygous
Athena Diagnostics Inc RCV000392246 SCV001476147 pathogenic not provided 2020-04-30 criteria provided, single submitter clinical testing Previously referred to as c.1277C>T (p.Pro426Leu) in published literature. The frequency of this variant in the general population is consistent with pathogenicity. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function.
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.
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille RCV001251909 SCV001427655 uncertain significance Intellectual disability 2019-01-01 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000392246 SCV001741563 pathogenic not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000392246 SCV001807480 pathogenic not provided no assertion criteria provided clinical testing

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