Submissions for variant NM_024312.5(GNPTAB):c.136C>T (p.Arg46Ter)

dbSNP: rs78347057

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000673315	SCV000798503	pathogenic	Mucolipidosis type II; Pseudo-Hurler polydystrophy	2018-03-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000760392	SCV000890264	pathogenic	not provided	2023-09-17	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20301728, 19617216, 24060719)
Invitae	RCV000673315	SCV002235710	pathogenic	Mucolipidosis type II; Pseudo-Hurler polydystrophy	2023-01-13	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs78347057, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Arg46*) 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 premature translational stop signal has been observed in individual(s) with mucolipidosis II (PMID: 19617216, 24060719). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 39031).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000032296	SCV003801183	pathogenic	Mucolipidosis type II	2023-01-13	criteria provided, single submitter	clinical testing	Variant summary: GNPTAB c.136C>T (p.Arg46X) 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 8e-06 in 251002 control chromosomes (gnomAD). c.136C>T has been reported in the literature as a biallelic genotype in multiple individuals affected with Mucolipidosis Type 2 (e.g. Cathey_2010, Alfadel_2013). These data indicate that the variant is very likely to be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000032296	SCV004801187	pathogenic	Mucolipidosis type II	2024-03-14	criteria provided, single submitter	research
GeneReviews	RCV000032296	SCV000055940	not provided	Mucolipidosis type II		no assertion provided	literature only
Natera, Inc.	RCV000032296	SCV001458990	pathogenic	Mucolipidosis type II	2020-09-16	no assertion criteria provided	clinical testing