Submissions for variant NM_000487.6(ARSA):c.257G>A (p.Arg86Gln)

gnomAD frequency: 0.00004  dbSNP: rs74315458

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723563	SCV000227131	pathogenic	not provided	2014-06-13	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000020316	SCV000893601	pathogenic	Metachromatic leukodystrophy	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV000020316	SCV000947631	pathogenic	Metachromatic leukodystrophy	2024-01-11	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 86 of the ARSA protein (p.Arg86Gln). This variant is present in population databases (rs74315458, gnomAD 0.02%). This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 1353340, 12809637, 18693274, 26462614). This variant is also known as c.251G>A, p.Arg84Gln. ClinVar contains an entry for this variant (Variation ID: 21186). 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%. Experimental studies have shown that this missense change affects ARSA function (PMID: 1353340). This variant disrupts the p.86 amino acid residue in ARSA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10477432, 18786133, 24001781, 26462614). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000020316	SCV001163458	pathogenic	Metachromatic leukodystrophy		criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000020316	SCV001934415	pathogenic	Metachromatic leukodystrophy	2021-02-10	criteria provided, single submitter	clinical testing	This variant was identified as homozygous.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000020316	SCV004020641	pathogenic	Metachromatic leukodystrophy	2023-06-28	criteria provided, single submitter	clinical testing	Variant summary: ARSA c.257G>A (p.Arg86Gln) results in a conservative amino acid change located in the N-terminal domain (IPR000917) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.1e-05 in 225598 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ARSA causing Metachromatic Leukodystrophy (7.1e-05 vs 0.0028), allowing no conclusion about variant significance. c.257G>A has been reported in the literature in multiple individuals affected with Metachromatic Leukodystrophy (e.g., Kappler_1992, Beerepoot_2020). 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, finding that the variant results in <10% of normal ARSA activity in BHK cells (e.g., Kappler_1992). The following publications have been ascertained in the context of this evaluation (PMID: 32632536, 1353340). Four submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000003205	SCV000023363	pathogenic	Metachromatic leukodystrophy, late-onset	1992-03-01	no assertion criteria provided	literature only
GeneReviews	RCV000020316	SCV000040691	not provided	Metachromatic leukodystrophy		no assertion provided	literature only
Natera, Inc.	RCV000020316	SCV001452358	pathogenic	Metachromatic leukodystrophy	2020-09-16	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000723563	SCV001743512	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000723563	SCV001798473	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000723563	SCV001926640	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000723563	SCV001965058	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000723563	SCV002037523	likely pathogenic	not provided		no assertion criteria provided	clinical testing