rs281864982

Positions:

• chr12-101765158-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_024312.5(GNPTAB):​c.1759C>T​(p.Arg587Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000274 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: GNPTAB NM_024312.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 6.19

Genes affected

GNPTAB (HGNC:29670): (N-acetylglucosamine-1-phosphate transferase subunits alpha and beta) This gene encodes two of three subunit types of the membrane-bound enzyme N-acetylglucosamine-1-phosphotransferase, a heterohexameric complex composed of two alpha, two beta, and two gamma subunits. The encoded protein is proteolytically cleaved at the Lys928-Asp929 bond to yield mature alpha and beta polypeptides while the gamma subunits are the product of a distinct gene (GeneID 84572). In the Golgi apparatus, the heterohexameric complex catalyzes the first step in the synthesis of mannose 6-phosphate recognition markers on certain oligosaccharides of newly synthesized lysosomal enzymes. These recognition markers are essential for appropriate trafficking of lysosomal enzymes. Mutations in this gene have been associated with both mucolipidosis II and mucolipidosis IIIA.[provided by RefSeq, May 2010]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-101765158-G-A is Pathogenic according to our data. Variant chr12-101765158-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 39040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101765158-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNPTAB	NM_024312.5	c.1759C>T	p.Arg587Ter	stop_gained	13/21	ENST00000299314.12	NP_077288.2
GNPTAB	XM_011538731.3	c.1678C>T	p.Arg560Ter	stop_gained	13/21		XP_011537033.1
GNPTAB	XM_006719593.4	c.1759C>T	p.Arg587Ter	stop_gained	13/19		XP_006719656.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNPTAB	ENST00000299314.12	c.1759C>T	p.Arg587Ter	stop_gained	13/21	1	NM_024312.5	ENSP00000299314	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461838 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727216

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000457 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pseudo-Hurler polydystrophy;C2673377:Mucolipidosis type II Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Nov 13, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 28, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 39040). This premature translational stop signal has been observed in individuals with mucolipidosis types II and III (PMID: 19617216, 23566849). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg587*) 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). -

Mucolipidosis type II Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 30, 2020	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Mucolipidosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 15, 2021

Variant summary: GNPTAB c.1759C>T (p.Arg587X) 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 was absent in 251420 control chromosomes. c.1759C>T has been reported in the literature in individuals affected with Mucolipidosis (example, Cathey_2010, Cury_2013, Velho_2015). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <2% of normal GlcNAc-1- phosphotransferase enzyme activity in HEK-293 cells overexpressing full-length WT or mutant /-subunit constructs (Velho_2015). Two 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	A
Vest4		0.96
GERP RS		5.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs281864982; hg19: chr12-102158936; COSMIC: COSV54779098; COSMIC: COSV54779098;