Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 428 of the ARSA protein (p.Pro428Leu). This variant is present in population databases (rs28940893, gnomAD 0.08%). This missense change has been observed in individuals with metachromatic leukodystrophy (MLD) (PMID: 1670590, 9090526, 9096767, 11941485, 26462614). ClinVar contains an entry for this variant (Variation ID: 3052). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ARSA function (PMID: 11777924, 11941485). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 06, 2021 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 12, 2019 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Feb 02, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with metachromatic leukodystrophy (MIM#250100). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2) for a recessive condition (105 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It has been reported as pathogenic in multiple individuals with metachromatic leukodystrophy (ClinVar, PMID: 26462614). (SP) 0903 - This variant has limited evidence for segregation with disease (PMID: 26462614). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. It was shown to result in deficiency of protein octamerisation, lack of stability in lysosomes and reduced enzymatic activity (PMID: 11777924). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Oct 10, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 03, 2022 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 04, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Aug 03, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 10, 2019 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 11, 2016 | - - |
not provided, no classification provided | in vitro | Gelb Laboratory, University of Washington | - | - - |