Submissions for variant NM_000487.6(ARSA):c.746T>C (p.Phe249Ser)

gnomAD frequency: 0.00001  dbSNP: rs199476384

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000524971	SCV000627145	pathogenic	Metachromatic leukodystrophy	2024-09-29	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 249 of the ARSA protein (p.Phe249Ser). This variant is present in population databases (rs199476384, gnomAD 0.003%). This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 14680985, 23701968, 24001781, 25965562, 26553228; internal data). 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.Phe247Ser. ClinVar contains an entry for this variant (Variation ID: 68149). Invitae Evidence 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
UniProtKB/Swiss-Prot	RCV000058980	SCV000090501	not provided	not provided		no assertion provided	not provided
Counsyl	RCV000524971	SCV000789820	likely pathogenic	Metachromatic leukodystrophy	2017-10-10	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000524971	SCV002081662	pathogenic	Metachromatic leukodystrophy	2020-09-03	no assertion criteria provided	clinical testing
Gelb Laboratory, University of Washington	RCV000524971	SCV005046556	not provided	Metachromatic leukodystrophy		no assertion provided	in vitro