ClinVar Miner

Submissions for variant NM_024312.5(GNPTAB):c.3565C>T (p.Arg1189Ter)

gnomAD frequency: 0.00001  dbSNP: rs137852897
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000723447 SCV000226963 pathogenic not provided 2014-06-02 criteria provided, single submitter clinical testing
Counsyl RCV000664622 SCV000788618 pathogenic Mucolipidosis type II; Pseudo-Hurler polydystrophy 2017-04-28 criteria provided, single submitter clinical testing
GeneDx RCV000723447 SCV000890263 pathogenic not provided 2018-09-10 criteria provided, single submitter clinical testing The R1189X nonsense variant in the GNPTAB gene has been reported previously in association with mucolipidosis II and III in several unrelated individuals who were homozygous for R1189X or heterozygous for R1189X and another variant in the GNPTAB gene (Paik et al., 2005; Otomo et al. 2009; Yang et al. 2017). The R1189X variant is a common pathogenic variant in several East Asian populations (Otomo et al. 2009). The R1189X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay.
Invitae RCV000664622 SCV001237189 pathogenic Mucolipidosis type II; Pseudo-Hurler polydystrophy 2024-01-31 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg1189*) in the GNPTAB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GNPTAB are known to be pathogenic (PMID: 19617216, 25107912). This variant is present in population databases (rs137852897, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with mucolipidosis II (PMID: 16116615, 23926388). ClinVar contains an entry for this variant (Variation ID: 2764). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193438 SCV001362264 pathogenic Mucolipidosis 2020-08-03 criteria provided, single submitter clinical testing Variant summary: GNPTAB c.3565C>T (p.Arg1189X) 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. The variant allele was found at a frequency of 2e-05 in 251436 control chromosomes. c.3565C>T has been reported in the literature in multiple individuals affected with Mucolipidosis (ML) in whom a diagnosis of ML was based on clinical manifestations and lysosomal enzyme activities in serum, lymphocyte and skin fibroblasts (example, Cathey_2010, Ma_2011, Otomo_2009). These data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Daryl Scott Lab, Baylor College of Medicine RCV003398424 SCV004102690 pathogenic GNPTAB-related disorder 2023-11-10 criteria provided, single submitter clinical testing
OMIM RCV000002891 SCV000023049 pathogenic Mucolipidosis type II 2009-03-01 no assertion criteria provided literature only
OMIM RCV000002892 SCV000023050 pathogenic Pseudo-Hurler polydystrophy 2009-03-01 no assertion criteria provided literature only
GeneReviews RCV000002892 SCV000054685 pathologic Pseudo-Hurler polydystrophy 2012-05-10 no assertion criteria provided curation Converted during submission to Pathogenic.
GeneReviews RCV000002891 SCV000055990 not provided Mucolipidosis type II no assertion provided literature only
Natera, Inc. RCV000002891 SCV001457937 pathogenic Mucolipidosis type II 2020-09-16 no assertion criteria provided clinical testing

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