Submissions for variant NM_000487.6(ARSA):c.293C>T (p.Ser98Phe)

gnomAD frequency: 0.00004  dbSNP: rs74315456

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723374	SCV000110804	pathogenic	not provided	2013-05-08	criteria provided, single submitter	clinical testing
Counsyl	RCV000020317	SCV000220940	likely pathogenic	Metachromatic leukodystrophy	2014-12-09	criteria provided, single submitter	literature only
Labcorp Genetics (formerly Invitae), Labcorp	RCV000020317	SCV001223293	pathogenic	Metachromatic leukodystrophy	2025-01-06	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 98 of the ARSA protein (p.Ser98Phe). This variant is present in population databases (rs74315456, gnomAD 0.007%). This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 1678251, 12809637, 22993277, 23701968). This variant is also known as c.287C>T, p.Ser96Phe. ClinVar contains an entry for this variant (Variation ID: 3054). 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%. Experimental studies have shown that this missense change affects ARSA function (PMID: 1678251). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000723374	SCV001245881	pathogenic	not provided	2017-08-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000020317	SCV001821473	pathogenic	Metachromatic leukodystrophy	2021-08-05	criteria provided, single submitter	clinical testing	Variant summary: ARSA c.293C>T (p.Ser98Phe) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.4e-05 in 208510 control chromosomes. c.293C>T has been reported in the literature in multiple individuals affected with Metachromatic Leukodystrophy (example, Gieselmann_1991, Rafi_2003, van Rappard_2016, Beerepoot_2020). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity in-vitro (example, Gieselmann_1991). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV000723374	SCV001825197	pathogenic	not provided	2019-10-14	criteria provided, single submitter	clinical testing	Published functional studies demonstrate loss of enzyme activity (Gieselmann et al., 1991); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 1678251, 12809637, 32632536, 7649558, 16546179)
Fulgent Genetics, Fulgent Genetics	RCV000020317	SCV002781876	likely pathogenic	Metachromatic leukodystrophy	2022-04-21	criteria provided, single submitter	clinical testing
OMIM	RCV000003199	SCV000023357	pathogenic	Metachromatic leukodystrophy, late infantile form	1989-12-01	no assertion criteria provided	literature only
GeneReviews	RCV000020317	SCV000040692	not provided	Metachromatic leukodystrophy		no assertion provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000723374	SCV001740349	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000723374	SCV001807962	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000723374	SCV001918284	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000723374	SCV001927583	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000723374	SCV001958314	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000020317	SCV002083906	pathogenic	Metachromatic leukodystrophy	2020-10-13	no assertion criteria provided	clinical testing
Gelb Laboratory, University of Washington	RCV000020317	SCV005046660	not provided	Metachromatic leukodystrophy		no assertion provided	in vitro