Submissions for variant NM_000487.6(ARSA):c.946G>A (p.Ala316Thr)

dbSNP: rs199476368

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000665708	SCV000789872	uncertain significance	Metachromatic leukodystrophy	2017-02-24	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000665708	SCV004300064	pathogenic	Metachromatic leukodystrophy	2022-11-13	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 68167). 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. For these reasons, this variant has been classified as Pathogenic. This variant is also known as A314T. This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 316 of the ARSA protein (p.Ala316Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 9090526).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004586532	SCV005076596	uncertain significance	not specified	2024-04-30	criteria provided, single submitter	clinical testing	Variant summary: ARSA c.946G>A (p.Ala316Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 239136 control chromosomes (gnomAD). c.946G>A has been reported in the literature in individuals affected with Metachromatic Leukodystrophy (Draghia_1997). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 9090526). ClinVar contains an entry for this variant (Variation ID: 68167). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000665708	SCV005656800	likely pathogenic	Metachromatic leukodystrophy	2024-05-03	criteria provided, single submitter	clinical testing
UniProtKB/Swiss-Prot	RCV000058999	SCV000090520	not provided	not provided		no assertion provided	not provided
Gelb Laboratory, University of Washington	RCV000665708	SCV005046507	not provided	Metachromatic leukodystrophy		no assertion provided	in vitro