Submissions for variant NM_000487.6(ARSA):c.251C>T (p.Pro84Leu) (rs6151411)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000672436	SCV000797541	uncertain significance	Metachromatic leukodystrophy	2018-02-05	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000672436	SCV000915007	uncertain significance	Metachromatic leukodystrophy	2018-03-05	criteria provided, single submitter	clinical testing	The ARSA c.251C>T (p.Pro84Leu) missense variant, historically described as p.Pro82Leu, has been reported two in studies. Barth et al. (1995) describe a child with late infantile arylsulfatase A deficiency, also known as metachromatic leukodystrophy, in whom the p.Pro84Leu variant was identified in a heterozygous state. A second variant was not detected. In 2008, Biffi et al. reported a child with early juvenile arylsulfatase A deficiency in whom the p.Pro84Leu was identified in trans with a second missense variant. The p.Pro84Leu variant was absent from 110 control chromosomes from healthy individuals, and is reported at a frequency of 0.000077 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the limited evidence, the p.Pro84Leu variant is classified as unknown significance but suspicious for pathogenicity for arylsulfatase A deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV000672436	SCV000947341	uncertain significance	Metachromatic leukodystrophy	2018-12-20	criteria provided, single submitter	clinical testing	This sequence change replaces proline with leucine at codon 84 of the ARSA protein (p.Pro84Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs6151411, ExAC 0.008%). This variant has been observed in an individual in combination with another ARSA rare variant (PMID: 18786133) and in individuals affected with this condition for whom the second allele was unknown (PMID: 7581401, 28762252). ClinVar contains an entry for this variant (Variation ID: 556430). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.