ClinVar Miner

Submissions for variant NM_000487.6(ARSA):c.465+1G>A (rs80338815)

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Total submissions: 27
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000335617 SCV000110808 pathogenic not provided 2015-08-06 criteria provided, single submitter clinical testing
GeneDx RCV000335617 SCV000329083 pathogenic not provided 2018-08-29 criteria provided, single submitter clinical testing The c.465+1G>A variant is a common pathogenic variant in central and western European populations associated with metachromatic leukodystrophy (MLD) with no functional arylsulfatase A activity and designated as an I-type (Infantile/juvenile-onset) ARSA allele (Polten et al., 1991; Biffi et al., 2008; Gomez-Ospina, 2017). The c.465+1G>A variant destroys the canonical splice donor site in intron 2, and is expected to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. We interpret c.465+1G>A as a pathogenic variant.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000335617 SCV000610089 pathogenic not provided 2017-04-24 criteria provided, single submitter clinical testing
Invitae RCV000020319 SCV000627142 pathogenic Metachromatic leukodystrophy 2020-11-02 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 2 of the ARSA gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs80338815, ExAC 0.1%). This variant has been reported in the literature in individuals affected with metachromatic leukodystrophy (PMID: 1670590, 18786133, 21167507, 26462614, 9090526, 11456299, 9600244, 7825603). This variant is also known in the literature as c.459+1G>A, IVS2+1G>A, and allele I or 0. ClinVar contains an entry for this variant (Variation ID: 3051). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ARSA are known to be pathogenic (PMID: 8962139, 10477432). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000020319 SCV000696808 pathogenic Metachromatic leukodystrophy 2017-05-21 criteria provided, single submitter clinical testing Variant summary: The ARSA c.465+1G>A variant involves the alteration of a conserved intronic nucleotide and 5/5 splice prediction tools predict a significant impact on normal splicing, which has been functionally supported (Zlotogora_1994 and Polten_1991). This variant was found in 88/111568 control chromosomes at a frequency of 0.0007888, which does not exceed the estimated maximal expected allele frequency of a pathogenic ARSA variant (0.0027951). Multiple publications have cited the variant in homozygous and compound heterozygous affected individuals diagnosed with late-, juvenile- and adult-onset depending on the second mutation in trans. The variant of interest has been indicated to be a common founder mutation (Zlotogora_1994 and Polten_1991). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000020319 SCV000893600 pathogenic Metachromatic leukodystrophy 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000020319 SCV000915006 pathogenic Metachromatic leukodystrophy 2018-12-18 criteria provided, single submitter clinical testing The ARSA c.465+1G>A variant, also referred to as c.459+1G>A, has been described as one of the most common pathogenic variants for arylsulfatase A deficiency occurring in the central and western European populations (Fluharty et al. 2006). Across a selection of the available literature, the c.465+1G>A variant has been identified in at least eight homozygotes, 16 compound heterozygotes, and 25 heterozygotes with an uncharacterized second allele, giving an allele frequency ranging from 7.5% to 37% in patients with arylsulfatase A deficiency (Polten et al. 1991; Eto et al. 1993; Draghia et al. 1997; Berger et al. 1997; Lugowska et al. 2005; Biffi et al. 2008; Shukla et al. 2011). Biochemical analyses indicate that the variant is associated with no residual arylsulfatase A activity (Polten et al. 1991). The c.465+1G>A variant is reported at a frequency of 0.00132 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the collective evidence, the c.465+1G>A variant is classified as pathogenic for arylsufatase A deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Mendelics RCV000020319 SCV001141463 pathogenic Metachromatic leukodystrophy 2019-05-28 criteria provided, single submitter clinical testing
Baylor Genetics RCV000020319 SCV001163457 pathogenic Metachromatic leukodystrophy criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000020319 SCV001194193 pathogenic Metachromatic leukodystrophy 2019-12-11 criteria provided, single submitter clinical testing NM_000487.5(ARSA):c.465+1G>A(aka IVS2+1G>A) is classified as pathogenic in the context of metachromatic leukodystrophy and is associated with the infantile form of this disease. Sources cited for classification include the following: PMID 1670590 and 8095918. Classification of NM_000487.5(ARSA):c.465+1G>A(aka IVS2+1G>A) is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.‚Äã
CeGaT Praxis fuer Humangenetik Tuebingen RCV000335617 SCV001245879 pathogenic not provided 2018-09-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000020319 SCV001366183 pathogenic Metachromatic leukodystrophy 2018-10-19 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2.
Institute of Human Genetics, University of Leipzig Medical Center RCV000020319 SCV001440246 pathogenic Metachromatic leukodystrophy 2019-01-01 criteria provided, single submitter clinical testing
Institute of Human Genetics,Cologne University RCV000020319 SCV001441231 pathogenic Metachromatic leukodystrophy 2020-09-30 criteria provided, single submitter research
Ambry Genetics RCV001267384 SCV001445565 pathogenic Inborn genetic diseases 2014-09-07 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000335617 SCV001447222 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000020319 SCV001448761 pathogenic Metachromatic leukodystrophy 2018-08-10 criteria provided, single submitter clinical testing
Centre for Inherited Metabolic Diseases, Karolinska University Hospital RCV000020319 SCV001519663 pathogenic Metachromatic leukodystrophy 2021-03-12 criteria provided, single submitter clinical testing
OMIM RCV000003192 SCV000023350 pathogenic Metachromatic leukodystrophy, juvenile type 2001-07-01 no assertion criteria provided literature only
OMIM RCV000003194 SCV000023352 pathogenic Metachromatic leukodystrophy, adult type 2001-07-01 no assertion criteria provided literature only
GeneReviews RCV000020319 SCV000040694 pathologic Metachromatic leukodystrophy 2011-08-25 no assertion criteria provided curation Converted during submission to Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000335617 SCV000801471 pathogenic not provided 2018-02-07 no assertion criteria provided clinical testing
GenomeConnect, ClinGen RCV000020319 SCV001423421 not provided Metachromatic leukodystrophy no assertion provided phenotyping only Variant interpretted as Pathogenic and reported on 05-17-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille RCV001251910 SCV001427656 uncertain significance Intellectual disability 2019-01-01 no assertion criteria provided clinical testing
Natera, Inc. RCV000020319 SCV001462391 pathogenic Metachromatic leukodystrophy 2020-09-16 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000335617 SCV001741313 pathogenic not provided no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000335617 SCV001800523 pathogenic not provided no assertion criteria provided clinical testing

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