Submissions for variant NM_000487.6(ARSA):c.656G>A (p.Arg219His)

gnomAD frequency: 0.00021  dbSNP: rs148403406

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000177070	SCV000228889	uncertain significance	not provided	2015-05-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222426	SCV002500479	uncertain significance	not specified	2023-12-07	criteria provided, single submitter	clinical testing	Variant summary: ARSA c.656G>A (p.Arg219His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 250704 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ARSA causing Metachromatic Leukodystrophy (5.6e-05 vs 0.0028), allowing no conclusion about variant significance. c.656G>A has been reported in the literature as a complex allele in cis with c.1108C>T (p.Arg370Trp) (also known as c.1114C>T, p.Arg372Trp) in at-least one individual with Metachromatic Leukodystrophy (MLD) who harbored c.1108C>T in isolation on the other allele (Grossi_2008). This supports the cis orientation of this variant. To our knowledge, this variant has not been reported in isolation in individuals affected with MLD. Therefore, these report(s) do not provide unequivocal conclusions about association of the variant with Metachromatic Leukodystrophy. Of note, c.1108C>T is well reported as a pathogenic/likely pathogenic ARSA variant associated with MLD. At least one publication reports experimental evidence evaluating an impact of this variant in isolation on protein function (example, Grossi_2008). The most pronounced variant effect results in 15.6% of normal ARSA enzyme activity in-vitro in transfected COS-7 cells. The following publications has been ascertained in the context of this evaluation (PMID: 26462614, 18693274). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002517709	SCV003276257	uncertain significance	Metachromatic leukodystrophy	2022-08-09	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 219 of the ARSA protein (p.Arg219His). This variant is present in population databases (rs148403406, gnomAD 0.07%). This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 18693274). This variant is also known as p.R217H. ClinVar contains an entry for this variant (Variation ID: 196276). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects ARSA function (PMID: 18693274). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Gelb Laboratory, University of Washington	RCV002517709	SCV005046575	not provided	Metachromatic leukodystrophy		no assertion provided	in vitro