Submissions for variant NM_024312.5(GNPTAB):c.616_619del (p.Thr206fs)

dbSNP: rs281865024

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000790767	SCV000231786	pathogenic	not provided	2013-08-28	criteria provided, single submitter	clinical testing
Counsyl	RCV000665595	SCV000789742	pathogenic	Mucolipidosis type II; Pseudo-Hurler polydystrophy	2017-02-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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	Mucolipidosis type II; Pseudo-Hurler polydystrophy	2023-12-12	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. Loss-of-function variants in GNPTAB are known to be pathogenic (PMID: 19617216, 25107912). This variant is present in population databases (rs398124399, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with mucolipidosis II and III (PMID: 16465621, 24798265). This variant is also known as FS211X (type 1), 773_776delCAGA. ClinVar contains an entry for this variant (Variation ID: 38432). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000790767	SCV003852931	pathogenic	not provided	2023-03-21	criteria provided, single submitter	clinical testing	Frameshift 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; Also known as FS211X; This variant is associated with the following publications: (PMID: 18190596, 16465621, 30882951, 24798265)
GeneReviews	RCV000031989	SCV000054690	pathologic	Mucolipidosis type II	2012-05-10	no assertion criteria provided	curation	Converted during submission to Pathogenic.
Natera, Inc.	RCV000031989	SCV001458987	pathogenic	Mucolipidosis type II	2020-09-16	no assertion criteria provided	clinical testing