Submissions for variant NM_000487.6(ARSA):c.938G>A (p.Arg313Gln)

gnomAD frequency: 0.00002  dbSNP: rs199476382

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000058997	SCV000521136	likely pathogenic	not provided	2016-08-29	criteria provided, single submitter	clinical testing	The R313Q variant in the ARSA gene, also known as R311Q using alternate nomenclature, has been reported previously in association with late-infantile metachromatic leukodystrophy in two siblings who were homozygous for R313Q (Shukla et al., 2011; Liaw et al., 2015) and in an affected individual who was heterozygous for R313Q as well as heterozygous for a second pathogenic variant in the ARSA gene (Biffi et al., 2008). The R313Q variant has also been reported in an individual with juvenile metachromatic leukodystrophy who was heterozygous for R313Q without an identified second pathogenic variant but who was also heterozygous for an ARSA pseudodeficiency allele (Barth et al., 1995). The R313Q variant was not observed in approximately 6,500 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 R313Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant at this same residue (R313P) as well as in nearby residues (G310V, G310D, G311S, E314D, A316T, A316D) have been reported in the Human Gene Mutation Database in association with metachromatic leukodystrophy (Stenson et al., 2014), supporting the functional importance of this region of the protein. The R313Q variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000984245	SCV001588979	pathogenic	Metachromatic leukodystrophy	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 313 of the ARSA protein (p.Arg313Gln). This variant is present in population databases (rs199476382, gnomAD 0.003%). This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 21167507, 28667691). This variant is also known as Arg311Gln. ClinVar contains an entry for this variant (Variation ID: 68165). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ARSA protein function with a positive predictive value of 95%. This variant disrupts the p.Arg313 amino acid residue in ARSA. Other variant(s) that disrupt this residue have been observed in individuals with ARSA-related conditions (PMID: 26462614), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000058997	SCV001715400	pathogenic	not provided	2020-07-16	criteria provided, single submitter	clinical testing	PS3, PS4_Moderate, PM2, PP4, PP3
Neuberg Centre For Genomic Medicine, NCGM	RCV000984245	SCV003803630	pathogenic	Metachromatic leukodystrophy		criteria provided, single submitter	clinical testing	The missense variant p.R313Q in ARSA (NM_000487.6) has been observed to be homozygous in individuals affected with metachromatic leukodystrophy (Shukla P et al; Gonorazky HD et al). Other variant(s) that disrupt this residue have been observed in individuals with ARSA-related conditions, indicating that the residue is functionally important(Cesani M et al). This variant was found in ClinVar (Variant 68165) with a classification of Pathogenic/Likely Pathogenic. The p.R313Q variant is observed in 1/29,832 (0.0034%) alleles from individuals of South Asian background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. In silico tools are contradictory in their predictions (SIFT-Tolerated, Polyphen- Damaging) and the residue is conserved across species. For these reasons, this variant has been classified as Pathogenic
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000984245	SCV003922684	pathogenic	Metachromatic leukodystrophy	2024-04-02	criteria provided, single submitter	clinical testing	Variant summary: ARSA c.938G>A (p.Arg313Gln) results in a conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.3e-06 in 241990 control chromosomes. c.938G>A has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Metachromatic Leukodystrophy (e.g. Barth_1995, Biffi_2008, Shukla_2011, Fumagalli_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no direct experimental evidence demonstrating an impact on protein function has been reported, although cells from homozygous or compound heterozygous patients showed little or no detectible ASA enzymatic activity (e.g. Biffi_2008, Shukla_2011). The following publications have been ascertained in the context of this evaluation (PMID: 21167507, 7581401, 18786133, 33855715). ClinVar contains an entry for this variant (Variation ID: 68165). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000984245	SCV005656802	pathogenic	Metachromatic leukodystrophy	2024-04-03	criteria provided, single submitter	clinical testing
UniProtKB/Swiss-Prot	RCV000058997	SCV000090518	not provided	not provided		no assertion provided	not provided
Counsyl	RCV000984245	SCV001132338	likely pathogenic	Metachromatic leukodystrophy	2018-12-13	no assertion criteria provided	clinical testing
Gelb Laboratory, University of Washington	RCV000984245	SCV005046509	not provided	Metachromatic leukodystrophy		no assertion provided	in vitro