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

gnomAD frequency: 0.00046  dbSNP: rs80338815

Total submissions: 40

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000335617	SCV000110808	pathogenic	not provided	2015-08-06	criteria provided, single submitter	clinical testing
GeneDx	RCV000335617	SCV000329083	pathogenic	not provided	2019-11-17	criteria provided, single submitter	clinical testing	Associated with no detectable arylsulfatase A activity (Gomez-Ospina et al. 2017); Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Previously reported as c.459+1G>A due to the use of alternate nomenclature; This variant is associated with the following publications: (PMID: 8095918, 25525159, 1670590, 18786133, 21167507, 7815434, 9600244, 11456299, 7825603, 9090526, 28923328, 20301309, 32632536, 31589614, 31418856, 31186049, 31980526, 33385934)
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	2024-01-31	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. Variants that disrupt the donor or acceptor splice site 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). This variant is present in population databases (rs80338815, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. Disruption of this splice site has been observed in individuals with metachromatic leukodystrophy (PMID: 1670590, 7825603, 9090526, 9600244, 11456299, 18786133, 21167507, 26462614). ClinVar contains an entry for this variant (Variation ID: 3051). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000335617	SCV000801471	pathogenic	not provided	2022-04-01	criteria provided, single submitter	clinical testing	PP4, PM2, PM3, PS4_moderate, PVS1
Fulgent Genetics, Fulgent Genetics	RCV000020319	SCV000893600	pathogenic	Metachromatic leukodystrophy	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, 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 Genetics, 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 Center for Human Genetics Tuebingen	RCV000335617	SCV001245879	pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	ARSA: PM3:Very Strong, PVS1, PM2, PS3:Supporting
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	2022-06-16	criteria provided, single submitter	clinical testing	The c.465+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 2 of the ARSA gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. This alteration (also known as c.459+1G>A) is one of the most common disease-causing mutations in patients with metachromatic leukodystrophy. In the homozygous state, this mutation is associated with the late-infantile form of disease whereas in the compound heterozygote state, its been associated with a less severe presentation (Comabella, 2001; Cesani, 2016; Draghia, 1997; Heinisch, 1995; Polten, 1991). This nucleotide position is highly conserved in available vertebrate species. Patients homozygous for this alteration were found to have extremely low ARSA enzyme activity in their peripheral mononuclear blood cells (Biffi, 2008). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic.
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
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000020319	SCV001984757	pathogenic	Metachromatic leukodystrophy		criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000020319	SCV001984802	pathogenic	Metachromatic leukodystrophy	2020-08-31	criteria provided, single submitter	clinical testing	This variant is also known in the literature as c.459+1G>A and IVS2+1G>A (PMID: 1670590, 18786133). This variant affects the canonical splice donor site of intron 2 and is therefore predicted to interfere with splicing and result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This alteration has been previously reported as a compound heterozygous change in patients with Arylsulfatase A Deficiency (also known as metachromatic leukodystrophy (MLD)) (PMID: 1670590, 18786133, 21167507, 26462614, 9090526, 11456299, 9600244, 7825603). Functional studies indicated that this variant leads to extremely low enzymatic activity (PMID: 18786133). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.062% (168/271628). It is one of the most common pathogenic variant causing early-onset (late infantile) MLD in individuals of central and western European ancestry (PMID: 1670590). Multiple splice prediction tools suggest this variant is likely to interfere with normal splicing. Based on the available evidence, the c.465+1G>A variant is classified as Pathogenic.
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	RCV001778645	SCV002016300	pathogenic	Neurodevelopmental disorder	2021-09-13	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000020319	SCV002018774	pathogenic	Metachromatic leukodystrophy	2022-06-03	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002251862	SCV002523090	pathogenic	See cases	2022-04-14	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1, PM3
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	RCV000020319	SCV002764723	pathogenic	Metachromatic leukodystrophy	2020-11-20	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000020319	SCV002767655	pathogenic	Metachromatic leukodystrophy	2022-02-02	criteria provided, single submitter	clinical testing	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) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. Exact protein consequence is unknown, however analysis of patient cells showed no residual protein (PMID: 1670590). (SP) 0251 - Variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (168 heterozygotes, 0 homozygotes). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0703 - Another canonical splice site variant (c.465+2T>A) has moderate previous evidence for pathogenicity, and has been reported as likely pathogenic (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in many unrelated individuals with metachromatic leukodystrophy (ClinVar, PMID: 28923328). (SP) 1001 - Strong functional evidence supporting abnormal protein function, where homozygous patient fibroblasts had no residual protein (PMID: 1670590). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000020319	SCV003922102	pathogenic	Metachromatic leukodystrophy	2023-05-02	criteria provided, single submitter	curation	The homozygous c.465+1G>A variant in ARSA was identified by our study in two siblings with metachromatic leukodystrophy. The c.465+1G>A variant in ARSA has been identified in 60 unrelated individuals with autosomal recessive metachromatic leukodystrophy (PMID: 11456299, PMID: 7825603, PMID: 9600244, PMID: 18786133, PMID: 15952986, PMID: 9096767, PMID: 9090526, PMID: 8455580, PMID: 8095918, PMID: 21167507, PMID: 7815434, PMID: 2574462, PMID: 1670590), but has been identified in 0.1% (140/121592) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs80338815). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 3051) and has been interpreted as pathogenic by multiple submitters. Of these 60 affected unrelated individuals, 35 were homozygotes (PMID: 7825603, PMID: 18786133, PMID: 15952986, PMID: 8455580, PMID: 8095918, PMID: 21167507, PMID: 7815434, PMID: 2574462, PMID: 1670590), 8 were compound heterozygotes who carried pathogenic or likely pathogenic variants in trans (PMID: 9090526, ClinVar ID: 3052; PMID: 9096767, ClinVar ID: 3052, ClinVar ID: 3057; PMID: 18786133, ClinVar Variation ID: 68144, ClinVar Variation ID: 840642, ClinVar Variation ID: 68126), 11 were presumed compound heterozygotes who carried pathogenic or likely pathogenic variants in unknown phase (PMID: 1670590, PMID: 8095918, ClinVar Variation ID: 3052; PMID: 15952986, ClinVar Variation ID: 3052, ClinVar ID: 3057; PMID: 9600244, ClinVar ID: 3057), and four were compound heterozygotes who carried variants of uncertain significance in trans (PMID: 9090526, ClinVar Variation ID: 68115; PMID: 18786133, ClinVar Variation ID: 68145; PMID: 11456299, ClinVar Variation ID: 3092), which increases the likelihood that the c.465+1G>A variant is pathogenic. In vitro functional studies provide some evidence that the c.465+1G>A variant may impact protein function (PMID: 2574462, PMID: 1670590). However, these types of assays may not accurately represent biological function. This variant is located in the 5' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. Loss of function of the ARSA gene is an established disease mechanism in autosomal recessive metachromatic leukodystrophy. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive metachromatic leukodystrophy. ACMG/AMP Criteria applied: PVS1, PM3_VeryStrong, PS3_Supporting (Richards 2015).
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000335617	SCV004026369	pathogenic	not provided	2023-05-03	criteria provided, single submitter	clinical testing	PVS1, PP5, PS3
Institute of Human Genetics, University Hospital of Duesseldorf	RCV000020319	SCV004046724	pathogenic	Metachromatic leukodystrophy		criteria provided, single submitter	not provided
PreventionGenetics, part of Exact Sciences	RCV003934795	SCV004756654	pathogenic	ARSA-related condition	2023-12-02	criteria provided, single submitter	clinical testing	The ARSA c.465+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been documented in both homozygous and compound heterozygous states as causative for metachromatic leukodystrophy in numerous patients (Polten et al. 1991. PubMed ID: 1670590; legacy nomenclature: c.459+1G>A, or “I allele”; Gort et al. 1999. PubMed ID: 10477432; Beerepoot et al. 2020. PubMed ID: 32632536). Functional studies support the deleterious effect of this variant (Biffi et al. 2008. PubMed ID: 18786133). This variant is reported in 0.12% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice donor site in ARSA are expected to be pathogenic. This variant is interpreted as pathogenic.
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	not provided	Metachromatic leukodystrophy		no assertion provided	literature only
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
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000335617	SCV001926691	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000335617	SCV001972269	pathogenic	not provided		no assertion criteria provided	clinical testing