Submissions for variant NM_000487.6(ARSA):c.938G>A (p.Arg313Gln) (rs199476382)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000058997	SCV000521136	likely pathogenic	not provided	2016-08-29	criteria provided, single submitter	clinical testing	The R313Q variant in the ARSA gene, also known as R311Q using alternate nomenclature, has been reported previously in association with late-infantile metachromatic leukodystrophy in two siblings who were homozygous for R313Q (Shukla et al., 2011; Liaw et al., 2015) and in an affected individual who was heterozygous for R313Q as well as heterozygous for a second pathogenic variant in the ARSA gene (Biffi et al., 2008). The R313Q variant has also been reported in an individual with juvenile metachromatic leukodystrophy who was heterozygous for R313Q without an identified second pathogenic variant but who was also heterozygous for an ARSA pseudodeficiency allele (Barth et al., 1995). The R313Q variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R313Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant at this same residue (R313P) as well as in nearby residues (G310V, G310D, G311S, E314D, A316T, A316D) have been reported in the Human Gene Mutation Database in association with metachromatic leukodystrophy (Stenson et al., 2014), supporting the functional importance of this region of the protein. The R313Q variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
UniProtKB/Swiss-Prot	RCV000058997	SCV000090518	not provided	not provided		no assertion provided	not provided
Counsyl	RCV000984245	SCV001132338	likely pathogenic	Metachromatic leukodystrophy	2018-12-13	no assertion criteria provided	clinical testing

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