ClinVar Miner

Submissions for variant NM_000487.6(ARSA):c.542T>G (p.Ile181Ser) (rs74315457)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000657846 SCV000228890 pathogenic not provided 2015-02-10 criteria provided, single submitter clinical testing
Invitae RCV000020320 SCV000627144 pathogenic Metachromatic leukodystrophy 2018-11-26 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with serine at codon 181 of the ARSA protein (p.Ile181Ser). The isoleucine residue is moderately conserved and there is a large physicochemical difference between isoleucine and serine. This variant is present in population databases (rs74315457, ExAC 0.05%). This variant is a common cause of metachromatic leukodystrophy in Europe and has been mainly associated with the juvenile and adult onset forms of the disease (PMID: 9096767, 12081727, 1684088, 26462614, 26890752). This variant is also known as c.536T>G, p.Ile179Ser in the literature. ClinVar contains an entry for this variant (Variation ID: 3057). Experimental studies have shown that this missense change abrogates ARSA enzymatic activity (PMID: 9600244, 1684088). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000020320 SCV000677953 likely pathogenic Metachromatic leukodystrophy 2015-06-06 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000020320 SCV000696809 pathogenic Metachromatic leukodystrophy 2017-03-19 criteria provided, single submitter clinical testing Variant summary: The ARSA c.542T>G (p.Ile181Ser) variant located in the alkaline phosphatase-like domain (via InterPro) involves the alteration of a conserved nucleotide, which 3/4 in silico tools (SNPs&GO not captured here due to low reliability index) predict a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 26/116786 (1/4492), which does not exceed the estimated maximal expected allele frequency of a pathogenic ARSA variant of 1/357. Multiple publications have cited the variant in affected individuals predominantly as compound heterozygotes and indicated to cause late-juvenile/adult onset MLD. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
GeneDx RCV000657846 SCV000779603 pathogenic not provided 2018-12-07 criteria provided, single submitter clinical testing The I181S variant in the ARSA gene has been reported previously in association with metachromatic leukodystrophy in individuals who were either homozygous or compound heterozygous for the variant (Stoeck et al., 2016; Barboura et al., 2011; Biffi et al., 2008; Fluharty et al., 1991). Functional studies show that I181S results in approximately 5% residual arylsulfatase A activity, compared to wildtype (Fluharty et al., 1991). The I181S variant is observed in 59/124526 (0.05%) alleles from individuals of non-Finnish European background in large population cohorts (Lek et al., 2016). We interpret I181S as a pathogenic variant.
Fulgent Genetics,Fulgent Genetics RCV000020320 SCV000893599 pathogenic Metachromatic leukodystrophy 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000020320 SCV000915004 pathogenic Metachromatic leukodystrophy 2018-11-01 criteria provided, single submitter clinical testing Across a selection of the available literature, the ARSA c.542T>G (p.Ile181Ser) missense variant, also reported as p.Ile179Ser, has been identified in 24 individuals with arylsulfatase A deficiency, or metachromatic leukodystrophy, including in a compound heterozygous state in 11 individuals and in a heterozygous state in 13 individuals (Fluharty et al. 1991; Berger et al. 1997; Gomez-Lira et al. 1998; Lugowska et al. 2005). Testing methodology in these studies typically assessed for common variants and lacked comprehensive analysis of the gene for rarer variants, which might explain the presence of the p.Ile181Ser variant in a heterozygous state. Segregation of the variant with the disease was shown in one study. The p.Ile181Ser variant was absent from at least 50 controls and is reported at a frequency of 0.000474 in the European (non-Finnish) population of the Genome Aggregation Database. Functional assays in cultured baby hamster kidney cells demonstrated the p.Ile181Ser variant had approximately 5% activity as compared to wild type (Fluharty et al. 1991). It is suggested that the p.Ile181Ser variant is associated with a late-onset phenotype, including juvenile-onset or adult-onset types (Berger et al. 1997; Lugowska et al. 2005). Based on the collective evidence, the p.Ile181Ser variant is classified as a pathogenic variant for arylsulfatase A deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
OMIM RCV000003202 SCV000023360 pathogenic Metachromatic leukodystrophy, juvenile type 2002-05-01 no assertion criteria provided literature only
OMIM RCV000003203 SCV000023361 pathogenic Metachromatic leukodystrophy, adult type 2002-05-01 no assertion criteria provided literature only
GeneReviews RCV000020320 SCV000040695 pathologic Metachromatic leukodystrophy 2011-08-25 no assertion criteria provided curation Converted during submission to Pathogenic.

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