Submissions for variant NM_000487.6(ARSA):c.737G>A (p.Arg246His)

gnomAD frequency: 0.00001  dbSNP: rs199476366

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000058979	SCV000110813	pathogenic	not provided	2013-07-03	criteria provided, single submitter	clinical testing
Counsyl	RCV000150061	SCV000790947	likely pathogenic	Metachromatic leukodystrophy	2017-04-17	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000150061	SCV001578267	pathogenic	Metachromatic leukodystrophy	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 246 of the ARSA protein (p.Arg246His). This variant is present in population databases (rs199476366, gnomAD 0.006%). This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 9090526, 22993277, 25965562, 26462614). This variant is also known as p.Arg244His. ClinVar contains an entry for this variant (Variation ID: 68148). 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 with a positive predictive value of 95%. This variant disrupts the p.Arg246 amino acid residue in ARSA. Other variant(s) that disrupt this residue have been observed in individuals with ARSA-related conditions (PMID: 2299327, 9090526), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000058979	SCV002818877	pathogenic	not provided	2022-12-28	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as R244H using alternate nomenclature; This variant is associated with the following publications: (PMID: 22993277, 27289174, 9090526, 25965562, 23845948, 26462614)
Revvity Omics, Revvity	RCV000150061	SCV003815633	pathogenic	Metachromatic leukodystrophy	2022-09-12	criteria provided, single submitter	clinical testing
UniProtKB/Swiss-Prot	RCV000058979	SCV000090500	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000150061	SCV002081663	pathogenic	Metachromatic leukodystrophy	2020-07-10	no assertion criteria provided	clinical testing
Gelb Laboratory, University of Washington	RCV000150061	SCV005046558	not provided	Metachromatic leukodystrophy		no assertion provided	in vitro