ClinVar Miner

Submissions for variant NM_000487.6(ARSA):c.979G>A (p.Gly327Ser) (rs148092995)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414752 SCV000490407 pathogenic not provided 2016-04-18 criteria provided, single submitter clinical testing The G327S variant in the ARSA gene has been previously reported in association with juvenile-onset MLD in two families where affected individuals were also heterozygous for another pathogenic variant in ARSA (Eng et. al, 2003; Cesani et al., 2015). This variant causes a non-conservative amino acid substituion in a conservative position and it is predicted to destroy the canonical splice donor site of intron 5. A missense variant in the same codon (G327C [G325C using alternative nomenclature]) is reported to cause aberrant splicing of ARSA mRNA (Gieselmann et. al, 1994). Therefore, we interpret G327S to be a pathogenic variant.
Invitae RCV000984246 SCV001588978 pathogenic Metachromatic leukodystrophy 2020-06-04 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 327 of the ARSA protein (p.Gly327Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant also falls at the last nucleotide of exon 5 of the ARSA coding sequence, which is part of the consensus splice site for this exon. This variant is present in population databases (rs148092995, ExAC 0.02%). This variant has been observed to be homozygous or in combination with another ARSA variant in individuals affected with metachromatic leukodystrophy (PMID: 14517960, 26462614, 28762252). This variant is also known in the literature as c.973G>A (p.Gly325Ser). ClinVar contains an entry for this variant (Variation ID: 372303). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000984246 SCV001132339 likely pathogenic Metachromatic leukodystrophy 2019-04-11 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.