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

Total submissions: 27

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