ClinVar Miner

Submissions for variant NM_000487.6(ARSA):c.449C>G (p.Pro150Arg) (rs199476375)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000698866 SCV000827555 likely pathogenic Metachromatic leukodystrophy 2020-01-20 criteria provided, single submitter clinical testing This sequence change replaces proline with arginine at codon 150 of the ARSA protein (p.Pro150Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported as homozygous in an individual affected with metachromatic leukodystrophy (PMID: 26462614, 30828547) as well as the presymptomatic sibling (PMID: 23845948). This variant is also known as p.Pro148Arg in the literature. ClinVar contains an entry for this variant (Variation ID: 576385). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). This variant disrupts the p.Pro150 amino acid residue in ARSA. Other variant(s) that disrupt this residue have been observed in individuals with ARSA-related conditions (PMID: 10381328, 18786133), which suggests that this may be a clinically significant amino acid residue. 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.

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