ClinVar Miner

Submissions for variant NM_000487.6(ARSA):c.746T>C (p.Phe249Ser) (rs199476384)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000524971 SCV000627145 likely pathogenic Metachromatic leukodystrophy 2016-12-20 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with serine at codon 249 of the ARSA protein (p.Phe249Ser). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and serine. This variant is present in population databases (rs199476384, ExAC 0.006%). This variant has been reported in three individuals affected with metachromatic leukodystrophy as compound heterozygous with other pathogenic variants (PMID: 14680985, 26553228, Invitae). All three individuals showed low leukocyte arylsulfatase A activity in leukocytes although in one of them the enzyme activity was confounded by the presence of a pseudodeficiency allele. ClinVar contains an entry for this variant (Variation ID: 68149). This variant is also known as p.Phe247Ser in the literature. In summary, this variant is a rare missense change that has been observed in affected individuals co-occurring with known ARSA pathogenic variants.  This evidence indicates that the variant is pathogenic, but additional functional or genetic data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
UniProtKB/Swiss-Prot RCV000058980 SCV000090501 not provided not provided no assertion provided not provided
Counsyl RCV000524971 SCV000789820 likely pathogenic Metachromatic leukodystrophy 2017-10-10 no assertion criteria provided clinical testing

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