rs34002892

chr12-101753469-TGA-T

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.3503_3504del(p.Leu1168GlnfsTer5) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000494 in 1,613,534 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00051 (0 hom.)
• Consequence: GNPTAB NM_024312.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:26 O:1
• Conservation: PhyloP100: 8.94

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 12-101753469-TGA-T is Pathogenic according to our data. Variant chr12-101753469-TGA-T is described in ClinVar as [Pathogenic]. Clinvar id is 2771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101753469-TGA-T is described in Lovd as [Pathogenic]. Variant chr12-101753469-TGA-T is described in Lovd as [Likely_pathogenic]. Variant chr12-101753469-TGA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNPTAB	NM_024312.5	c.3503_3504del	p.Leu1168GlnfsTer5	frameshift_variant	19/21	ENST00000299314.12
GNPTAB	XM_011538731.3	c.3422_3423del	p.Leu1141GlnfsTer5	frameshift_variant	19/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNPTAB	ENST00000299314.12	c.3503_3504del	p.Leu1168GlnfsTer5	frameshift_variant	19/21	1	NM_024312.5	P1
GNPTAB	ENST00000549738.5	c.*110_*111del		3_prime_UTR_variant, NMD_transcript_variant	4/5	4

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000513 AC: 129 AN: 251354 Hom.: 0 AF XY: 0.000471 AC XY: 64 AN XY: 135836

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000751

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000660

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000508 AC: 743 AN: 1461234 Hom.: 0 AF XY: 0.000494 AC XY: 359 AN XY: 726984

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000559

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000846

Gnomad4 FIN exome AF: 0.000168

Gnomad4 NFE exome AF: 0.000536

Gnomad4 OTH exome AF: 0.000596

GnomAD4 genome AF: 0.000355 AC: 54 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21 AN XY: 74478

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000588

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000327 Hom.: 0

Bravo AF: 0.000363

EpiCase AF: 0.00115

EpiControl AF: 0.000533

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:26 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucolipidosis type II Pathogenic:12 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 25, 2014	The p.Leu1168GlnfsX5 mutation is the most common mucolipidosis II alpha/beta mutation worldwide and has also been shown to cause Mucolipidosis IIIA in the compound heterozygous state, in combination with mild mutations (Kudo, 2006, summarized in De Pace 2013). This variant has been identified in 0.06% (5/8254) of European American chromosomes and 0.047% (2/4264) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs34002892), consistent with recessive carrier frequencies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1168 and leads to a premature termination codon 5 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. In summary, this variant meets our criteria to be classified as pathogenic for Mucolipidosis II alpha/beta in an autosomal recessive manner. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Nov 18, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000002771, PMID:16465621). The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0005511). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Oct 06, 2021	PVS1, PM2, PP3, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 22, 2016	Variant summary: The GNPTAB c.3503_3504delTC (p.Leu1168Glnfs) 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.3410T>A/p.Leu1137X). One in silico tool predicts a damaging outcome for this variant. This variant was found in 66/121350 control chromosomes at a frequency of 0.0005439, which does not exceed the estimated maximal expected allele frequency of a pathogenic GNPTAB variant (0.0022361). This variant has been reported in many affected individuals both as homozygotes and compound heterozygotes. Functional studies showed that this variant led to nearly non-detectable level of enzyme activity. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Aug 05, 2022	ACMG classification criteria: PVS1 very strong, PS4 strong, PM3 moderated -
Pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Aug 04, 2022	A homozygous single base pair deletion in exon 22 of the GNTPAB gene that results in a frameshift and premature truncation of the protein 5 amino acids downstream to codon 1168, (p.Leu1168Glnfs*5 ;ENST00000299314.12) was detected. This variant has not been reported in the 1000 genomes and gnomAD databases and has a minor allele frequency of 0.001% in our internal database. The in silico prediction of the variant is damaging MutationTaster2. The reference region is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -

not provided Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 25, 2022	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; This variant is associated with the following publications: (PMID: 25788519, 16465621, 18190596, 21228398, 25606425, 20880125, 24375680, 27710913, 27785713, 28918368, 29289611, 23566849, 16630736, 24685522, 19659762, 25107912, 30209781, 30548430, 29620724, 29704188, 30105123, 22570975, 31038846, 19617216, 31618753, 32651481, 32036093, 34426522, 33594065, 31589614, 33083013, 32981126, 31758855, 33854947) -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 08, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 02, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 23, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	GNPTAB: PVS1, PM3:Strong, PM2 -

Pseudo-Hurler polydystrophy Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2011	- -
Pathogenic, no assertion criteria provided	curation	GeneReviews	May 10, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 24, 2019	NM_024312.4(GNPTAB):c.3503_3504delTC(L1168Qfs*5) is classified as pathogenic in the context of GNPTAB-related disorders. Sources cited for classification include the following: PMID 24375680, 16465621, 20880125 and 21228398. Classification of NM_024312.4(GNPTAB):c.3503_3504delTC(L1168Qfs*5) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.‚Äã -

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

Pathogenic, criteria provided, single submitter	clinical testing;provider interpretation	Geisinger Autism and Developmental Medicine Institute, Geisinger Health System	Apr 27, 2017	This 9 year old male with autism spectrum disorder, intellectual disability, severe irritability, premature adrenarche, and macrocephaly was found to carry a paternally inherited variant in GNPTAB. This variant has been reported in association with mucolipidosis II, which is inherited in an autosomal recessive fashion. Because this patient lacks the majority of the features of ML II, clinical correlation is felt to be very poor. His father is also unaffected. This indicates likely carrier status. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change creates a premature translational stop signal (p.Leu1168Glnfs*5) 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 (rs34002892, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individuals with mucolipidosis (PMID: 16465621, 20880125, 24375680, 25606425, 27710913). This variant is also known as 3665_3666delTC, FS1172X. ClinVar contains an entry for this variant (Variation ID: 2771). For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 15, 2021

The c.3503_3504delTC (p.L1168Qfs*5) alteration, located in exon 19 (coding exon 19) of the GNPTAB gene, consists of a deletion of 2 nucleotides from position 3503 to 3504, causing a translational frameshift with a predicted alternate stop codon after 5 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, this alteration has an overall frequency of 0.05% (139/282744) total alleles studied. The highest observed frequency was 0.08% (23/30614) of South Asian alleles. This common disease-causing alteration (referred to as FS1172X in some publications) is well described in the literature and has been reported in the homozygous and compound heterozygous states in many individuals with GNTAB-related disorders (Alegra, 2014; Coutinho, 2011; Kudo, 2006). Functional studies showed that this alteration results in a loss of GlcNAc-1-phosphotransferase activity (Kudo, 2006; Velho, 2015). Based on the available evidence, this alteration is classified as pathogenic. -

GNPTAB-Related Disorders Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

The GNPTAB c.3503_3504delTC (p.Leu1168GlnfsTer5) variant results in a frameshift, and is therefore predicted to result in premature termination of the protein. The variant is well described in the literature and is the most common pathogenic variant for for GNPTAB-related disorders in several populations, usually associated with a severe phenotype. Across a selection of the available literature the p.Leu1168GlnfsTer5 variant has been identified in a total of 100 patients with GNPTAB-related disorders, including 51 in a homozygous state, 47 in a compound heterozygous state, and two in a heterozygous state (Kudi et al. 2006; Bargal et al. 2006; Encarnacao et al. 2009; Cathey et al. 2010; Coutinho et al. 2011; Cury et al. 2013; Aggarwal et al. 2014). The variant has also been found in a heterozygous state in at least 22 healthy individuals (Kudo et al. 2006; Coutinho et al. 2011). Coutinho et al. (2011) demonstrated the high frequency of the variant was due to a founder effect. Plante et al. (2008) identified the variant in 27/27 obligate carriers from the Saguenay-Lac-Saint-Jean region of Quebec, which has the highest carrier rate of mucolipidosis type II in the world at 1/39, and demonstrated that this was also due to a founder effect. The variant was absent from 95 control individuals in the above studies but is reported at a frequency of 0.00085 in the South Asian population of the Exome Aggregation Consortium. Functional studies demonstrated that the variant does produce a truncated protein that is retained in the ER and not transported to the Golgi, and therefore does not form a mature subunit (De Pace et al. 2014). The p.Leu1168GlnfsTer5 variant has also been shown to result in absent or significantly decreased enzyme activity in patient fibroblasts (Kudo et al. 2006; Encarnacao et al. 2009; Velho et al. 2015). Due to the potential impact of frameshift variants and the collective evidence from the literature, the p.Leu1168GlnfsTer5 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. -

Computational scores

Source: dbNSFP v4.3

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: rs34002892; hg19: chr12-102147247;