Submissions for variant NM_000487.6(ARSA):c.739G>A (p.Gly247Arg)

dbSNP: rs74315471

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723992	SCV000230102	pathogenic	not provided	2014-05-29	criteria provided, single submitter	clinical testing
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	RCV000020321	SCV000680146	pathogenic	Metachromatic leukodystrophy	2017-09-08	criteria provided, single submitter	clinical testing
Counsyl	RCV000020321	SCV000799561	likely pathogenic	Metachromatic leukodystrophy	2018-05-01	criteria provided, single submitter	clinical testing
Suma Genomics	RCV000020321	SCV001847682	likely pathogenic	Metachromatic leukodystrophy		criteria provided, single submitter	clinical testing
Invitae	RCV000020321	SCV002211356	pathogenic	Metachromatic leukodystrophy	2023-01-01	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ARSA function (PMID: 8101083). 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. ClinVar contains an entry for this variant (Variation ID: 3074). This variant is also known as p.Gly245Arg. This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 8101083, 26553228, 31186049). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs74315471, gnomAD 0.003%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 247 of the ARSA protein (p.Gly247Arg).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000020321	SCV002557411	pathogenic	Metachromatic leukodystrophy	2022-06-24	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with metachromatic leukodystrophy (MIM#250100). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 3 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Gly247Glu) has been reported in a compound heterozygote individual with metachromatic leukodystrophy (PMID: 27779215). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least six homozygote or compound heterozygote individuals with metachromatic leukodystrophy; and consistently classified as pathogenic by diagnostic laboratories in ClinVar (PMIDs: 31186049, 21167507). This variant is also known as p.(Gly245Arg) in older manuscripts. (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
GeneDx	RCV000723992	SCV003194954	pathogenic	not provided	2023-08-10	criteria provided, single submitter	clinical testing	Published functional studies demonstrate G247R does not induce enzyme activity (Hasegawa et al., 1993); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.(G245R) due to use of alternate nomenclature; This variant is associated with the following publications: (PMID: 26553228, 8101083, 21167507, 31186049, 36789546)
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000020321	SCV004101546	pathogenic	Metachromatic leukodystrophy		criteria provided, single submitter	clinical testing	The missense c.739G>A (p.Gly247Arg) variant has been observed in individual(s) with metachromatic leukodystrophy (Liaw HR et al). Experimental studies have shown that this missense change affects ARSA function (Hasegawa Y et al). 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) indicates that this missense variant is expected to disrupt ARSA protein function. This variant is reported with the allele frequency (0.0012%) in the gnomad and novel in 1000 genome database. It has been submitted to ClinVar as Pathogenic. The amino acid Gly at position 247 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000020321	SCV004801942	pathogenic	Metachromatic leukodystrophy	2024-03-23	criteria provided, single submitter	clinical testing	A heterozygous missense variant in exon 4 of the ARSA gene that results in the amino acid substitution of Arginine for Glycine at codon 247 was detected. The observed variant c.739G>A has not been reported in the 1000 genomes and has a MAF of 0.0012% in the gnomAD database. The in silico prediction of the variant is damaging by MutationTaster2, SIFT, PolyPhen2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic.
OMIM	RCV000003220	SCV000023378	pathogenic	Metachromatic leukodystrophy, severe	1993-07-01	no assertion criteria provided	literature only
GeneReviews	RCV000020321	SCV000040697	not provided	Metachromatic leukodystrophy		no assertion provided	literature only