ClinVar Miner

Submissions for variant NM_000487.6(ARSA):c.338T>C (p.Leu113Pro)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001376979 SCV001574194 likely pathogenic Metachromatic leukodystrophy 2020-08-14 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 113 of the ARSA protein (p.Leu113Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in individual(s) with clinical features of metachromatic leukodystrophy (PMID: 28799099, Invitae). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx RCV001574994 SCV001801901 likely pathogenic not provided 2019-12-17 no assertion criteria provided clinical testing Not observed at a significant frequency or in the homozygous state in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28799099)

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