Submissions for variant NM_000487.6(ARSA):c.842C>T (p.Thr281Ile)

dbSNP: rs966673017

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Revvity Omics, Revvity	RCV001785964	SCV002021436	likely pathogenic	Metachromatic leukodystrophy	2020-10-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001785964	SCV003444613	pathogenic	Metachromatic leukodystrophy	2024-02-19	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 281 of the ARSA protein (p.Thr281Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 17413447). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as p.Thr279Ileu. ClinVar contains an entry for this variant (Variation ID: 1323931). 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%. For these reasons, this variant has been classified as Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV001785964	SCV005438714	likely pathogenic	Metachromatic leukodystrophy	2023-07-22	criteria provided, single submitter	clinical testing	The observed missense variant c.842C>Tp.Thr281Ile in ARSA gene has been reported previously in a family with metachromatic leukodystrophy Kumperscak HG, et al., 2007. The p.Thr281Ile variant is absent in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. Multiple lines of computational evidence SIFT-damaging and Mutation Taster-disease causing predict a damaging effect on protein structure and function for this variant. The amino acid Thr at position 281 is changed to a Ile changing protein sequence and it might alter its composition and physico-chemical properties. The reference amino acid p.Thr281Ile in ARSA is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. However, study on multiple affected individuals and functional impact of the variant is not available. For these reasons, this variant has been classified as variant of Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005237987	SCV005886393	uncertain significance	not specified	2025-02-17	criteria provided, single submitter	clinical testing	Variant summary: ARSA c.842C>T (p.Thr281Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250456 control chromosomes. c.842C>T has been reported in the literature in two siblings affected with Metachromatic Leukodystrophy (Kumperscak_2007). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 17413447). ClinVar contains an entry for this variant (Variation ID: 1323931). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Gelb Laboratory, University of Washington	RCV001785964	SCV005046534	not provided	Metachromatic leukodystrophy		no assertion provided	in vitro