ClinVar Miner

Submissions for variant NM_000487.6(ARSA):c.769G>C (p.Asp257His) (rs80338819)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255092 SCV000322398 pathogenic not provided 2016-08-02 criteria provided, single submitter clinical testing The D257H variant in the ARSA gene has been reported previously, using alternate nomenclature D255H, in two unrelated Belgian families with late infantile MLD who were compound heterozygous for D257H and a second splice site variant (Lissens et al., 1996). The D257H variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The D257H variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Functional studies of D257H indicate that it creates an abnormal protein with folding deficits that cause it to be retained in the endoplasmic reticulum (Poeppel et al., 2005). We interpret D257H as a pathogenic variant.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000255092 SCV000331188 pathogenic not provided 2015-11-12 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000020322 SCV000696810 pathogenic Metachromatic leukodystrophy 2016-06-25 criteria provided, single submitter clinical testing Variant summary: The c.769G>C (p.Asp257His) in ARSA gene is a missense change that involves a highly conserved nucleotide and 5/5 in silico tools predict deleterious outcome. The variant is absent from the control population dataset of ExAC. The variant was identified in multiple affected individuals presented with enzymatically confirmed infantile and juvenile forms of MLD with undetectable levels of arylsulfatase A activity in fibroblasts or severely reduced levels in leucocytes. The variant of interest has been reported as Pathogenic by reputable database/clinical laboratory. Taking together, the variant was classified as Pathogenic.
Invitae RCV000020322 SCV000945104 pathogenic Metachromatic leukodystrophy 2020-10-25 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with histidine at codon 257 of the ARSA protein (p.Asp257His). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be homozygous or in combination with another ARSA variant in individuals affected with metachromatic leukodystrophy (PMID: 8982952, 10477432, 12445909). This variant is also known in the literature as D255H. ClinVar contains an entry for this variant (Variation ID: 21187). Experimental studies have shown that this missense change abrogates ARSA activity and disrupts protein trafficking (PMID: 8982952, 15720392). For these reasons, this variant has been classified as Pathogenic.
GeneReviews RCV000020322 SCV000040698 pathologic Metachromatic leukodystrophy 2011-08-25 no assertion criteria provided curation Converted during submission to Pathogenic.
Counsyl RCV000020322 SCV001132336 likely pathogenic Metachromatic leukodystrophy 2015-07-21 no assertion criteria provided clinical testing

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