ClinVar Miner

Submissions for variant NM_000487.6(ARSA):c.917C>T (p.Thr306Met) (rs199476359)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute of Human Genetics,Klinikum rechts der Isar RCV000578460 SCV000680145 pathogenic Metachromatic leukodystrophy 2017-09-08 criteria provided, single submitter clinical testing
Counsyl RCV000578460 SCV000800270 uncertain significance Metachromatic leukodystrophy 2018-05-29 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000578460 SCV001370552 pathogenic Metachromatic leukodystrophy 2020-05-05 criteria provided, single submitter clinical testing Variant summary: ARSA c.917C>T (p.Thr306Met) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain (IPR000917) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 247446 control chromosomes (gnomAD). c.917C>T has been reported in the literature in individuals affected with Metachromatic Leukodystrophy (e.g. Biffi_2008, Chen_2018, Li_2018). These data indicate that the variant is likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated null residual enzyme activity for the variant in different cellular systems (Cesani_2009). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=1) and as uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000578460 SCV001398115 likely pathogenic Metachromatic leukodystrophy 2019-09-03 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 306 of the ARSA protein (p.Thr306Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in combination with another ARSA variant in individual(s) with metachromatic leukodystrophy (PMID: 18786133, 30057904). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 911C>T (Thr304Met) in the literature. ClinVar contains an entry for this variant (Variation ID: 68159). This variant has been reported to affect ARSA protein function (PMID: 19606494). 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.
UniProtKB/Swiss-Prot RCV000058991 SCV000090512 not provided not provided no assertion provided not provided

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