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

Total submissions: 12

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	2018-12-19	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.
Counsyl	RCV000020319	SCV000677978	pathogenic	Metachromatic leukodystrophy	2015-06-14	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	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.
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 Genetic Testing Laboratories,Mayo Clinic	RCV000335617	SCV000801471	pathogenic	not provided	2018-02-07	no assertion criteria provided	clinical testing