ClinVar Miner

Submissions for variant NM_000202.8(IDS):c.851C>T (p.Pro284Leu)

gnomAD frequency: 0.00005  dbSNP: rs782286857
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000899427 SCV001043693 benign Mucopolysaccharidosis, MPS-II 2024-01-03 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002271596 SCV002556015 likely benign not specified 2022-06-02 criteria provided, single submitter clinical testing Variant summary: IDS c.851C>T (p.Pro284Leu) 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 allele was found at a frequency of 8.7e-05 in 183363 control chromosomes, predominantly at a frequency of 0.0012 within the East Asian subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in IDS causing Mucopolysaccharidosis Type II (Hunter Syndrome) (8.7e-05 vs 0.0029), allowing no conclusion about variant significance. c.851C>T has been reported in the literature as a pseudo-deficiency allele that has been associated with an attenuated phenotype in at-least one individual reportedly affected with Mucopolysaccharidosis Type II (Hunter Syndrome) (example, Kosuga_2016) and as a VUS in settings of newborn screening (NBS) among infants not meeting the confirmatory criteria for a typical MPS II diagnosis (example, Yu Lin_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Mucopolysaccharidosis Type II (Hunter Syndrome). At least one publication reports experimental evidence evaluating an impact on protein function (Yu Lin_2020). The most pronounced variant effect results in 62% of normal activity. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign. Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics RCV002444996 SCV002679144 likely benign Inborn genetic diseases 2018-02-14 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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