rs34002892
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_024312.5(GNPTAB):c.3503_3504delTC(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
Consequence
NM_024312.5 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| GNPTAB | NM_024312.5 | c.3503_3504delTC | p.Leu1168GlnfsTer5 | frameshift_variant | Exon 19 of 21 | ENST00000299314.12 | NP_077288.2 | |
| GNPTAB | XM_011538731.3 | c.3422_3423delTC | p.Leu1141GlnfsTer5 | frameshift_variant | Exon 19 of 21 | XP_011537033.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| GNPTAB | ENST00000299314.12 | c.3503_3504delTC | p.Leu1168GlnfsTer5 | frameshift_variant | Exon 19 of 21 | 1 | NM_024312.5 | ENSP00000299314.7 | ||
| GNPTAB | ENST00000549738.5 | n.*110_*111delTC | non_coding_transcript_exon_variant | Exon 4 of 5 | 4 | ENSP00000450161.1 | ||||
| GNPTAB | ENST00000549738.5 | n.*110_*111delTC | 3_prime_UTR_variant | Exon 4 of 5 | 4 | ENSP00000450161.1 |
Frequencies
GnomAD3 genomes 0.000355 AC: 54AN: 152182Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000513 AC: 129AN: 251354Hom.: 0 AF XY: 0.000471 AC XY: 64AN XY: 135836
GnomAD4 exome AF: 0.000508 AC: 743AN: 1461234Hom.: 0 AF XY: 0.000494 AC XY: 359AN XY: 726984
GnomAD4 genome 0.000355 AC: 54AN: 152300Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21AN XY: 74478
ClinVar
Submissions by phenotype
Mucolipidosis type II Pathogenic:14Other:1
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This variant has been previously reported as most frequently found pathogenic mutation in individuals affected with mucolipidosis II and III alpha/beta. The variant is located at the region that codes for the β subunit of phosphotransferase, has been associated with the severe phenotype when found in homozygosity or when found in heterozygosity with nonsense mutations or frameshift mutations [PMID: 23566849, 18190596]. -
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PVS1, PM2, PP3, PP5 -
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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 -
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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. -
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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. -
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. -
ACMG classification criteria: PVS1 very strong, PS4 strong, PM3 moderated -
not provided Pathogenic:9
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GNPTAB: PVS1, PM3:Strong, PM2 -
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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) -
PM2_moderate, PS3, PVS1 -
Pseudo-Hurler polydystrophy Pathogenic:5
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 -
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PVS1, PM3 (moderate),PM2 -
The frameshift variant c.3503_3504del (p.Leu1168GlnfsTer5) in the GNPTAB gene has been reported previously in homozygous state in multiple individuals affected with Mucolipidosis Type II and Type III. It is the most common variant. This variant is reported with the allele frequency (0.04%) in the gnomAD Exomes. It is submitted to ClinVar as Likely Pathogenic/ Pathogenic (Multiple submitters). This variant causes a frameshift starting with codon Leucine 1168, changes this amino acid to Glutamine residue, and creates a premature Stop codon at position 5 of the new reading frame. This variant is predicted to cause a loss of normal protein function through protein truncation. Loss of function variants has been previously reported to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pseudo-Hurler polydystrophy;C2673377:Mucolipidosis type II Pathogenic:3
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. -
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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. -
Inborn genetic diseases Pathogenic:1
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 disorder Pathogenic:1
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at