Submissions for variant NM_000487.6(ARSA):c.925G>A (p.Glu309Lys)

gnomAD frequency: 0.00004  dbSNP: rs199476360

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001039188	SCV001202704	pathogenic	Metachromatic leukodystrophy	2023-09-27	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 68162). 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. Experimental studies have shown that this missense change affects ARSA function (PMID: 19606494, 27904824, 28762252). For these reasons, this variant has been classified as Pathogenic. This variant is also known as p.Glu307Lys. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 309 of the ARSA protein (p.Glu309Lys). This variant is present in population databases (rs199476360, gnomAD 0.008%). This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 18768108, 19606494, 26462614, 30057904). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant.
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV001039188	SCV001573212	pathogenic	Metachromatic leukodystrophy		criteria provided, single submitter	clinical testing
GeneDx	RCV000058994	SCV001875120	pathogenic	not provided	2021-08-20	criteria provided, single submitter	clinical testing	In vitro assays of E309K demonstrate that this variant abolishes ARSA activity (Cesani et al., 2009; Ozkan et al., 2016; Bohringer et al., 2017); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as E307K; This variant is associated with the following publications: (PMID: 28762252, 26462614, 33855715, Hassannejad_2020, 32875726, 30057904, 33385934, 19606494, 27904824, 18768108)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001039188	SCV004020642	pathogenic	Metachromatic leukodystrophy	2023-06-16	criteria provided, single submitter	clinical testing	Variant summary: ARSA c.925G>A (p.Glu309Lys) results in a conservative amino acid change in 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 4.1e-06 in 246094 control chromosomes (gnomAD). c.925G>A has been reported in the literature as a biallelic genotype in multiple individuals affected with Metachromatic Leukodystrophy (e.g. Biffi_2008, Cesani_2015, Guo_2020, Santhanakumaran_2022). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function in vitro and found the variant effect results in <10% of normal activity, even when overexpressed (e.g. Cesani_2009, Bohringer_2017). The following publications have been ascertained in the context of this evaluation (PMID: 18786133, 19606494, 26462614, 32875726, 36240581, 28762252). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000058994	SCV004155286	pathogenic	not provided	2023-11-01	criteria provided, single submitter	clinical testing	ARSA: PM3:Very Strong, PM1, PM2, PM5, PS3:Supporting
UniProtKB/Swiss-Prot	RCV000058994	SCV000090515	not provided	not provided		no assertion provided	not provided