ClinVar Miner

Submissions for variant NM_024312.5(GNPTAB):c.612_615ACAG[1] (p.Thr206fs) (rs281865024)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000790767 SCV000231786 pathogenic not provided 2013-08-28 criteria provided, single submitter clinical testing
Counsyl RCV000665595 SCV000789742 pathogenic I cell disease; Pseudo-Hurler polydystrophy 2017-02-21 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780318 SCV000917485 pathogenic Mucolipidosis 2018-03-22 criteria provided, single submitter clinical testing Variant summary: GNPTAB c.616_619delACAG (p.Thr206TyrfsX6) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.1090C>T (p.Arg364X), c.1123C>T (p.Arg375X), c.1581delC (p.Cys528fsX19)). The variant allele was found at a frequency of 4.9e-05 in 245984 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in GNPTAB causing Mucolipidosis (4.9e-05 vs 2.20e-03), allowing no conclusion about variant significance. c.616_619delACAG has been reported in the literature in two individuals affected with Mucolipidosis type 2 (Kudo 2006). These data indicate that the variant may be associated with disease. This publication also reports experimental evidence evaluating an impact on protein function by measuring N-acetylglucosamine-phosphotransferase activity in cell lysates from fibroblasts or lymphoblasts derived from subjects. The most pronounced variant effect results in <1% of normal enzymatic activity. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000665595 SCV000944593 pathogenic I cell disease; Pseudo-Hurler polydystrophy 2018-11-06 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Thr206Tyrfs*6) in the GNPTAB gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs398124399, ExAC 0.04%). This variant has been observed in several individuals affected with mucolipidosis II and III  (PMID: 16465621, 24798265). This variant is also known as FS211X (type 1), 773_776delCAGA in the literature. ClinVar contains an entry for this variant (Variation ID: 38432). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Loss-of-function variants in GNPTAB are known to be pathogenic (PMID: 19617216, 25107912). For these reasons, this variant has been classified as Pathogenic.
GeneReviews RCV000031989 SCV000054690 pathologic I cell disease 2012-05-10 no assertion criteria provided curation Converted during submission to Pathogenic.

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