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

gnomAD frequency: 0.00002  dbSNP: rs148092995

Total submissions: 6

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	2023-08-22	criteria provided, single submitter	clinical testing	An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 327 of the ARSA protein (p.Gly327Ser). This variant also falls at the last nucleotide of exon 5, which is part of the consensus splice site for this exon. This variant is present in population databases (rs148092995, gnomAD 0.008%). This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 14517960, 26462614, 28762252). This variant is also known as c.973G>A (p.Gly325Ser). ClinVar contains an entry for this variant (Variation ID: 372303). Variants that disrupt 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. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000984246	SCV002500424	pathogenic	Metachromatic leukodystrophy	2022-03-16	criteria provided, single submitter	clinical testing	Variant summary: ARSA c.979G>A (p.Gly327Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. As the variant alters a conserved nucleotide located at the end of exon adjacent to the canonical splice donor site, several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.3e-05 in 223840 control chromosomes. c.979G>A has been reported in the literature as homozygous and compound heterozygous genotypes in multiple individuals affected with Metachromatic leukodystrophy (example, Eng_2003, Virgens_2015, Bohringer_2017, Abtahi_2022). These data indicate that the variant is very likely to 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 Arylsulfatase enzyme activity with increased urinary sulfatides at diagnosis (example, Bohringer_2017). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV002523904	SCV003549520	pathogenic	Inborn genetic diseases	2021-06-30	criteria provided, single submitter	clinical testing	The c.979G>A (p.G327S) alteration is located in exon 5 (coding exon 5) of the ARSA gene. This alteration results from a G to A substitution at nucleotide position 979, causing the glycine (G) at amino acid position 327 to be replaced by a serine (S). This change occurs in the last base pair of coding exon5, which makes it likely to have some effect on normal mRNA splicing. This mutation has been reported in the compound heterozygous state in several individuals with metachromatic leukodystrophy (Kreysing, 1993; Bern&aacute;, 2004; Luzi, 2013; Cesani, 2016). Based on the available evidence, this alteration is classified as pathogenic.
Revvity Omics, Revvity	RCV000984246	SCV003817895	likely pathogenic	Metachromatic leukodystrophy	2021-12-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000984246	SCV001132339	likely pathogenic	Metachromatic leukodystrophy	2019-04-11	no assertion criteria provided	clinical testing