Submissions for variant NM_000487.6(ARSA):c.931G>A (p.Gly311Ser)

gnomAD frequency: 0.00003  dbSNP: rs74315459

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000666302	SCV000790571	likely pathogenic	Metachromatic leukodystrophy	2017-04-04	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000666302	SCV000923448	pathogenic	Metachromatic leukodystrophy	2024-02-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000666302	SCV001198547	pathogenic	Metachromatic leukodystrophy	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 311 of the ARSA protein (p.Gly311Ser). This variant is present in population databases (rs74315459, gnomAD 0.01%). This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 8101038, 26462614, 28670130). 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 Gly309Ser. ClinVar contains an entry for this variant (Variation ID: 3060). 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%. Experimental studies have shown that this missense change affects ARSA function (PMID: 8101038). For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000666302	SCV001429286	pathogenic	Metachromatic leukodystrophy	2019-05-13	criteria provided, single submitter	clinical testing	This variant was identified as homozygous
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001813940	SCV001755533	pathogenic	Abnormality of the nervous system	2021-07-10	criteria provided, single submitter	clinical testing
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000666302	SCV001963619	pathogenic	Metachromatic leukodystrophy		criteria provided, single submitter	clinical testing
GeneDx	RCV002286693	SCV002576955	pathogenic	not provided	2022-09-30	criteria provided, single submitter	clinical testing	Published functional studies demonstrate G309S results in a significant reduction in enzyme activity (Kreysing et al., 1993; Bhringer et al., 2017); Not observed at 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 p.G309S; This variant is associated with the following publications: (PMID: 8101038, 15326627, 33385934, 27289174, 28762252, 33547378, 33855715, 34426522, 33726816, 27535533)
CeGaT Center for Human Genetics Tuebingen	RCV002286693	SCV005092872	pathogenic	not provided	2024-07-01	criteria provided, single submitter	clinical testing	ARSA: PM3:Strong, PM1, PM2, PM5, PS3:Supporting
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000666302	SCV005328383	pathogenic	Metachromatic leukodystrophy	2024-09-26	criteria provided, single submitter	clinical testing
OMIM	RCV000003206	SCV000023364	pathogenic	Metachromatic leukodystrophy, late infantile form	1993-08-01	no assertion criteria provided	literature only
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000714802	SCV000845536	uncertain significance	Pseudoarylsulfatase A deficiency	2018-08-07	flagged submission	clinical testing
Myelin Disorders Clinic-Children's Medical Center/Medical Genetics Lab-Tarbiat Modares University, Children's Medical Center, Pediatrics Center of Excellence,	RCV000666302	SCV001426665	uncertain significance	Metachromatic leukodystrophy		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000666302	SCV002081649	pathogenic	Metachromatic leukodystrophy	2020-07-03	no assertion criteria provided	clinical testing
Gelb Laboratory, University of Washington	RCV000666302	SCV005046510	not provided	Metachromatic leukodystrophy		no assertion provided	in vitro