Submissions for variant NM_000487.6(ARSA):c.929G>A (p.Gly310Asp)

dbSNP: rs199476356

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000695949	SCV000824490	pathogenic	Metachromatic leukodystrophy	2023-08-16	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 310 of the ARSA protein (p.Gly310Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of metachromatic leukodystrophy (PMID: 10477432; 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 also known as p.Gly308Asp. ClinVar contains an entry for this variant (Variation ID: 68163). 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. This variant disrupts the p.Gly310 amino acid residue in ARSA. Other variant(s) that disrupt this residue have been observed in individuals with ARSA-related conditions (PMID: 8891236, 10477432; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004799773	SCV005421959	uncertain significance	not specified	2024-10-28	criteria provided, single submitter	clinical testing	Variant summary: ARSA c.929G>A (p.Gly310Asp) 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 244576 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.929G>A has been reported in the literature in one individual affected with Metachromatic Leukodystrophy (Gort_1999). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 10477432). ClinVar contains an entry for this variant (Variation ID: 68163). Based on the evidence outlined above, the variant was classified as uncertain significance.
UniProtKB/Swiss-Prot	RCV000058995	SCV000090516	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000695949	SCV001462383	uncertain significance	Metachromatic leukodystrophy	2020-09-16	no assertion criteria provided	clinical testing