Submissions for variant NM_000487.6(ARSA):c.1492dup (p.Arg498fs)

dbSNP: rs774153480

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000411861	SCV000487285	likely pathogenic	Metachromatic leukodystrophy	2016-11-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000411861	SCV000916521	likely pathogenic	Metachromatic leukodystrophy	2018-12-20	criteria provided, single submitter	clinical testing	Variant summary: ARSA c.1492dupC (p.Arg498ProfsX75) causes a frameshift which results in an extension of the protein. The variant allele was found at a frequency of 4.7e-06 in 214108 control chromosomes. c.1492dupC has been reported in the literature in two related individuals affected with Metachromatic Leukodystrophy (Lugowska_2009). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10% of normal activity (Lugowska_2009). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae	RCV000411861	SCV001421807	pathogenic	Metachromatic leukodystrophy	2023-06-16	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this frameshift affects ARSA function (PMID: 19021637). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 371650). This variant is also known as g.2590_2591dupC. This frameshift has been observed in individual(s) with metachromatic leukodystrophy (PMID: 19021637, 26462614). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change results in a frameshift in the ARSA gene (p.Arg498Profs*75). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 12 amino acid(s) of the ARSA protein and extend the protein by 62 additional amino acid residues.
Suma Genomics	RCV000411861	SCV001847686	pathogenic	Metachromatic leukodystrophy		criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001821136	SCV002064474	likely pathogenic	not provided	2019-02-04	criteria provided, single submitter	clinical testing	DNA sequence analysis of the ARSA gene demonstrated a one base pair duplication in exon 8, c.1492dup. This duplication is predicted to result in an amino acid frameshift and creates a premature stop codon 74 amino acids downstream of the variant, p.Arg498Profs*75. This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated ARSA protein with potentially abnormal function. While this duplication has not been previously described in the literature, other duplications and deletions in the exon 8 of the ARSA gene have been described in patients with ARSA-related disorders. The c.1492dup sequence change has been described in the gnomAD database with a low population frequency of 0.00047%(dbSNP rs774153480).