Submissions for variant NM_000487.6(ARSA):c.869G>A (p.Arg290His)

gnomAD frequency: 0.00011  dbSNP: rs199476355

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Fulgent Genetics, Fulgent Genetics	RCV000668693	SCV000893597	likely pathogenic	Metachromatic leukodystrophy	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000668693	SCV000935212	pathogenic	Metachromatic leukodystrophy	2025-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 290 of the ARSA protein (p.Arg290His). This variant is present in population databases (rs199476355, gnomAD 0.02%). This missense change has been observed in individuals with metachromatic leukodystrophy (PMID: 10477432, 12809637, 15139291, 26462614). This variant is also known as R288H. ClinVar contains an entry for this variant (Variation ID: 68153). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ARSA protein function with a positive predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ARSA function (PMID: 15139291). This variant disrupts the p.Arg290 amino acid residue in ARSA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7866401, 16678723, 17560502, 19815439, 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000668693	SCV000966819	pathogenic	Metachromatic leukodystrophy	2020-09-11	criteria provided, single submitter	clinical testing	The p.Arg290His variant in ARSA (also described as p.Arg288His in the literature) has been reported in the compound heterozygous state in at least 5 individuals with metachromatic leukodystrophy (Gort 1999 PMID: 10477432, Rafi 2003 PMID: 12809637, Yaghootfam 2004 PMID:15139291, Cesani 2016 PMID: 26462614), 4 of whom had another disease-causing variant on the other copy of the ARSA gene. In these 4 individuals, the variant occurred on the background (in cis) of a pseudodeficiency allele (Gort 1999 PMID: 10477432, Rafi 2003 PMID: 12809637). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 68153) and has been identified in 0.02% (23/112038) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies using both patient fibroblasts and cultured cells show that this variant reduces enzyme activity (~2%), supporting an impact on protein function (Gort 1999 PMID: 10477432, Yaghootfam 2004 PMID:15139291). Computational prediction tools and conservation analyses also support an impact the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive metachromatic leukodystrophy. ACMG/AMP Criteria applied: PM3_Very Strong, PS3_Moderate, PP3.
Baylor Genetics	RCV000668693	SCV001163456	pathogenic	Metachromatic leukodystrophy		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000668693	SCV001194123	likely pathogenic	Metachromatic leukodystrophy	2020-01-06	criteria provided, single submitter	clinical testing	NM_000487.5(ARSA):c.869G>A(R290H) is classified as likely pathogenic in the context of metachromatic leukodystrophy. Sources cited for classification include the following: PMID 26462614, 12809637, 15139291 and 10477432. Classification of NM_000487.5(ARSA):c.869G>A(R290H) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000668693	SCV001361600	pathogenic	Metachromatic leukodystrophy	2019-12-31	criteria provided, single submitter	clinical testing	Variant summary: ARSA c.869G>A (p.Arg290His) results in a non-conservative amino acid change located in the Sulfatase, N-terminal (IPT000917) 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 0.00012 in 248178 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ARSA causing Metachromatic Leukodystrophy (0.00012 vs 0.0028), allowing no conclusion about variant significance. c.869G>A has been reported in the literature in individuals affected with Metachromatic Leukodystrophy (example, Gort_1999, Rafi_2003, Yaghooftam_2004, Cesani_2015). These data indicate that the variant is 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 40% of normal activity in a heterologous experimental system (Yaghooftam_2004). Four 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 (n=1)/likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV000058984	SCV001788925	likely pathogenic	not provided	2024-12-30	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Also known as p.R288H; This variant is associated with the following publications: (PMID: 26462614, 12809637, 15139291, 10477432, 31589614, 30609409, 37480112)
Revvity Omics, Revvity	RCV000668693	SCV002018797	pathogenic	Metachromatic leukodystrophy	2021-04-09	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004019068	SCV004908590	likely pathogenic	Inborn genetic diseases	2022-05-12	criteria provided, single submitter	clinical testing	The c.869G>A (p.R290H) 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 869, causing the arginine (R) at amino acid position 290 to be replaced by a histidine (H). Based on data from gnomAD, the A allele has an overall frequency of 0.01% (29/248178) total alleles studied. The highest observed frequency was 0.02% (23/112038) of European (non-Finnish) alleles. This alteration has been detected in the homozygous state and as compound heterozygous in trans with other pathogenic ARSA alterations in multiple unrelated individuals with metachromatic leukodystrophy with enzymatic activity levels are reduced to <5% in patient fibroblasts compared to healthy controls (Cesani, 2016; Yaghootfam, 2004; Rafi, 2003; Gort, 1999; Guo, 2020). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000668693	SCV005368481	pathogenic	Metachromatic leukodystrophy	2023-10-13	criteria provided, single submitter	clinical testing	Criteria applied: PM3_VSTR,PM5_STR,PS4_SUP,PM2_SUP,PP3
UniProtKB/Swiss-Prot	RCV000058984	SCV000090505	not provided	not provided		no assertion provided	not provided
PreventionGenetics, part of Exact Sciences	RCV003905027	SCV004729440	likely pathogenic	ARSA-related disorder	2023-12-02	no assertion criteria provided	clinical testing	The ARSA c.869G>A variant is predicted to result in the amino acid substitution p.Arg290His. This variant has been reported in the compound heterozygous state in several individuals with metachromatic leukodystrophy (Reported as R288H in Gort et al. 1999. PubMed ID: 10477432; Rafi et al. 2003. PubMed ID: 12809637; Cesani et al. 2015. PubMed ID: 26462614). A different amino acid substitution at this same position (c.868C>A, Arg290Ser) has also been reported in patients with metachromatic leukodystrophy (Reported as R288S in Luzi et al. 2013. PubMed ID: 24001781). This variant is reported in 0.021% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic.
Gelb Laboratory, University of Washington	RCV000668693	SCV005046525	not provided	Metachromatic leukodystrophy		no assertion provided	in vitro