Submissions for variant NM_000487.6(ARSA):c.256C>T (p.Arg86Trp)

gnomAD frequency: 0.00001  dbSNP: rs199476352

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000409776	SCV001229305	pathogenic	Metachromatic leukodystrophy	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 86 of the ARSA protein (p.Arg86Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 10477432, 18786133). This variant is also known as c.399C>T, p.R84W. ClinVar contains an entry for this variant (Variation ID: 68126). 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.Arg86 amino acid residue in ARSA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1353340, 12809637, 18693274, 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.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV001090098	SCV001245562	uncertain significance	Frontotemporal dementia	2019-10-28	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000409776	SCV002051321	pathogenic	Metachromatic leukodystrophy	2021-12-22	criteria provided, single submitter	clinical testing	Variant summary: ARSA c.256C>T (p.Arg86Trp) 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. The variant was absent in 225598 control chromosomes (gnomAD). The variant, c.256C>T (aka. c250C>T (Arg84Trp)) has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Metachromatic Leukodystrophy (e.g. Biffi_2008, Fumagalli_2021). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated about 6% residual activity (Biffi_2008, Cesani_2009). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar, and classified the variant as pathogenic (n=2) or VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV000409776	SCV002060223	pathogenic	Metachromatic leukodystrophy	2021-11-16	criteria provided, single submitter	clinical testing	NM_000487.5(ARSA):c.256C>T(R86W) is a missense variant classified as pathogenic in the context of metachromatic leukodystrophy. R86W has been observed in cases with relevant disease (PMID: 10477432, 18786133, 31694723, 26462614, 25965562, 23559313, 16678723, 26131420). Functional assessments of this variant are available in the literature (PMID: 18786133). R86W has been observed in population frequency databases (gnomAD: NFE 0.007%). In summary, NM_000487.5(ARSA):c.256C>T(R86W) is a missense variant that has functional support for pathogenicity and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
UniProtKB/Swiss-Prot	RCV000058956	SCV000090477	not provided	not provided		no assertion provided	not provided