Submissions for variant NM_000487.6(ARSA):c.1010A>T (p.Asp337Val)

gnomAD frequency: 0.00006  dbSNP: rs74315475

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169024	SCV000220172	likely pathogenic	Metachromatic leukodystrophy	2014-03-20	criteria provided, single submitter	literature only
GeneDx	RCV000413321	SCV000490408	pathogenic	not provided	2021-11-18	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect with no functional arylsulfatase A activity (Hess et al., 1996); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 14517960, 29915382, 8723680, 20339381, 7866401)
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000414806	SCV000492921	pathogenic	Leukodystrophy	2015-03-13	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000169024	SCV000593420	pathogenic	Metachromatic leukodystrophy	2016-02-11	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169024	SCV000836843	pathogenic	Metachromatic leukodystrophy	2024-10-28	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 337 of the ARSA protein (p.Asp337Val). This variant is present in population databases (rs74315475, gnomAD 0.008%). This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 7866401, 8723680, 10381328, 14517960, 20339381). 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 Asp335Val. ClinVar contains an entry for this variant (Variation ID: 3080). 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: 8723680). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000169024	SCV001163454	pathogenic	Metachromatic leukodystrophy		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169024	SCV001360433	pathogenic	Metachromatic leukodystrophy	2021-08-24	criteria provided, single submitter	clinical testing	Variant summary: ARSA c.1010A>T (p.Asp337Val) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain of 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 204330 control chromosomes (gnomAD). c.1010A>T has been reported in the literature in multiple individuals affected with Metachromatic Leukodystrophy (example: Lugowska_2010, Eng_2003, Qu_1999, Hess_1996). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant to cause a complete loss of catalytic activity of the enzyme (Hess_1996). Eight ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000169024	SCV001369264	pathogenic	Metachromatic leukodystrophy	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic.
Revvity Omics, Revvity	RCV000169024	SCV002018819	pathogenic	Metachromatic leukodystrophy	2022-09-13	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000413321	SCV002563738	pathogenic	not provided	2023-11-01	criteria provided, single submitter	clinical testing	ARSA: PM3:Very Strong, PM2, PS3:Supporting
Fulgent Genetics, Fulgent Genetics	RCV000169024	SCV002806807	pathogenic	Metachromatic leukodystrophy	2024-01-23	criteria provided, single submitter	clinical testing
OMIM	RCV000003226	SCV000023384	pathogenic	METACHROMATIC LEUKODYSTROPHY, SEVERE	2018-11-07	no assertion criteria provided	literature only
Mayo Clinic Laboratories, Mayo Clinic	RCV000413321	SCV000801467	pathogenic	not provided	2018-02-07	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000169024	SCV001462380	pathogenic	Metachromatic leukodystrophy	2020-09-16	no assertion criteria provided	clinical testing
Gelb Laboratory, University of Washington	RCV000169024	SCV005046801	not provided	Metachromatic leukodystrophy		no assertion provided	in vitro