Submissions for variant NM_000487.6(ARSA):c.641C>T (p.Ala214Val)

gnomAD frequency: 0.00006  dbSNP: rs74315467

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723836	SCV000228887	pathogenic	not provided	2014-06-13	criteria provided, single submitter	clinical testing
Counsyl	RCV000003216	SCV000486818	pathogenic	Metachromatic leukodystrophy	2016-08-18	criteria provided, single submitter	clinical testing
Invitae	RCV000003216	SCV001235946	pathogenic	Metachromatic leukodystrophy	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 214 of the ARSA protein (p.Ala214Val). This variant is present in population databases (rs74315467, gnomAD 0.004%). This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 7906588, 9090526, 9192271, 14517960, 26462614). This variant is also known as p.Ala212Val. ClinVar contains an entry for this variant (Variation ID: 3070). 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: 9192271). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000003216	SCV001360435	pathogenic	Metachromatic leukodystrophy	2019-09-07	criteria provided, single submitter	clinical testing	Variant summary: ARSA c.641C>T (p.Ala214Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250702 control chromosomes. c.641C>T has been reported in the literature in multiple individuals affected with Metachromatic Leukodystrophy (Barth_1993, Gort_1999, Eng_2003, Luzi_2013, Cesani_2015). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 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.
OMIM	RCV000003216	SCV000023374	pathogenic	Metachromatic leukodystrophy	1993-12-01	no assertion criteria provided	literature only
GeneReviews	RCV000003216	SCV000040696	not provided	Metachromatic leukodystrophy		no assertion provided	literature only
Natera, Inc.	RCV000003216	SCV001462385	pathogenic	Metachromatic leukodystrophy	2020-09-16	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000723836	SCV001744911	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000723836	SCV001931552	pathogenic	not provided		no assertion criteria provided	clinical testing