ClinVar Miner

Submissions for variant NM_024312.5(GNPTAB):c.1123C>T (p.Arg375Ter) (rs397507447)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000669771 SCV000794554 pathogenic I cell disease; Pseudo-Hurler polydystrophy 2017-09-28 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000790711 SCV000225069 pathogenic not provided 2013-02-20 criteria provided, single submitter clinical testing
GeneReviews RCV000032287 SCV000055931 pathologic I cell disease 2012-05-10 no assertion criteria provided curation Converted during submission to Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000349727 SCV000375432 pathogenic GNPTAB-Related Disorders 2017-08-29 criteria provided, single submitter clinical testing The GNPTAB c.1123C>T (p.Arg375Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. The variant has been reported in three studies in which it is found in a total of seven patients with mucolipidosis type II and mucolipidosis type III alpha/beta, including in one in a homozygous state, five in a compound heterozygous state, and one in a heterozygous state with a possible second unidentified variant (Tappino et al. 2009; Cathey et al. 2010; Cury et al. 2013). The p.Arg375Ter variant was also found in a heterozygous state in one parent whose affected status was not specified (Cury et al. 2013). Control data are unavailable for this variant, which is reported at a frequency of 0.0001 in the European (non-Finnish) population of the Exome Aggregation Consortium. Using Western blot analysis in COS-7 cells, Tappino et al. (2009) demonstrated that the p.Arg375Ter variant protein had a lower molecular weight compared to wild type protein. Due to the potential impact of stop-gained variants and evidence from the literature, the p.Arg375Ter variant is classified as pathogenic for GNPTAB-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000032287 SCV000699472 pathogenic I cell disease 2017-06-15 criteria provided, single submitter clinical testing Variant summary: The GNPTAB c.1123C>T (p.Arg375X) variant results in a premature termination codon, predicted to cause a truncated or absent GNPTAB 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 (e.g. c.1581delC, p.Cys528fsX19; c.2693delA, p.Lys898fsX13). One in silico tool predicts a damaging outcome for this variant. This variant was found in 7/121384 control chromosomes at a frequency of 0.0000577, which does not exceed the estimated maximal expected allele frequency of a pathogenic GNPTAB variant (0.0022361). The variant has been reported in multiple affected individuals in the literature both as homozygote and compound heterozygotes, and was shown in an in vitro study to produce a much smaller protein of about 50kDa in size, consistent with the synthesis of a severely truncated protein product that is unlikely to have retained any functional activity (Tappino_2009). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

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