Submissions for variant NM_000487.6(ARSA):c.1289T>C (p.Leu430Pro)

dbSNP: rs199476392

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000058949	SCV002758952	likely pathogenic	not provided	2022-12-01	criteria provided, single submitter	clinical testing	Reported previously in a patient with juvenile metachromatic leukodystrophy who harbored a second variant in the ARSA gene; phase unknown (Cesani et al., 2015); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.L428P; This variant is associated with the following publications: (PMID: 26462614, 18693274, 26659599, 27915290, 9272717)
Labcorp Genetics (formerly Invitae), Labcorp	RCV002514296	SCV003513262	pathogenic	Metachromatic leukodystrophy	2023-08-25	criteria provided, single submitter	clinical testing	This variant is also known as p.L428P. For these reasons, this variant has been classified as Pathogenic. 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: 68119). This missense change has been observed in individual(s) with clinical features of metachromatic leukodystrophy (PMID: 9272717, 26462614; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 430 of the ARSA protein (p.Leu430Pro).
Revvity Omics, Revvity	RCV002514296	SCV003825024	uncertain significance	Metachromatic leukodystrophy	2021-08-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002514296	SCV005422698	pathogenic	Metachromatic leukodystrophy	2024-10-18	criteria provided, single submitter	clinical testing	Variant summary: ARSA c.1289T>C (p.Leu430Pro; also described as c.1283T>C, p.L428P in the literature) 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 244162 control chromosomes (gnomAD). c.1289T>C has been reported in the literature in individuals (both homozygous and compound heterozygotes) affected with metachromatic leukodystrophy (examples: Regis_1997, Cesani_2015, Grossi_2008, Internal data). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 9272717, 26462614, 18693274). ClinVar contains an entry for this variant (Variation ID: 68119). Based on the evidence outlined above, the variant was classified as pathogenic.
UniProtKB/Swiss-Prot	RCV000058949	SCV000090470	not provided	not provided		no assertion provided	not provided
Gelb Laboratory, University of Washington	RCV002514296	SCV005046743	not provided	Metachromatic leukodystrophy		no assertion provided	in vitro