ClinVar Miner

Submissions for variant NM_024312.5(GNPTAB):c.3501_3502TC[1] (p.Leu1168fs) (rs34002892)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 18
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000082192 SCV000226964 pathogenic not provided 2015-12-08 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000002899 SCV000245616 pathogenic Mucolipidosis type II 2014-11-25 criteria provided, single submitter clinical testing 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.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000082192 SCV000281219 pathogenic not provided 2015-02-02 criteria provided, single submitter clinical testing
GeneDx RCV000082192 SCV000321745 pathogenic not provided 2017-11-03 criteria provided, single submitter clinical testing The c.3503_3504delTC pathogenic variant in the GNPTAB gene has been widely reported in association with mucolipidosis II in individuals from diverse ethnic backgrounds (Kudo et al., 2006, Coutinho et al., 2011; Alegra et al., 2014). A male infant homozygous for the c.3503_3504delTC variant exhibited GlcNAc-phosphotransferase enzyme activity that was < 0.1% of normal levels (Kudo et al., 2006). The c.3503_3504delTC variant causes a frameshift starting with codon Leucine 1168, changes this amino acid to a Glutamine residue and creates a premature Stop codon at position 5 of the new reading frame, denoted p.Leu1168GlnfsX5. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.3503_3504delTC variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.3503_3504delTC as a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000380090 SCV000375390 pathogenic GNPTAB-Related Disorders 2017-04-27 criteria provided, single submitter clinical testing 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.
Integrated Genetics/Laboratory Corporation of America RCV000002899 SCV000699482 pathogenic Mucolipidosis type II 2016-09-22 criteria provided, single submitter clinical testing 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.
Ambry Genetics RCV000623507 SCV000741655 pathogenic Inborn genetic diseases 2014-09-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Geisinger Autism and Developmental Medicine Institute,Geisinger Health System RCV000678389 SCV000804458 pathogenic Mucolipidosis type II; Pseudo-Hurler polydystrophy 2017-04-27 criteria provided, single submitter provider interpretation 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.
Invitae RCV000678389 SCV000824094 pathogenic Mucolipidosis type II; Pseudo-Hurler polydystrophy 2019-11-25 criteria provided, single submitter clinical testing 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. This variant is present in population databases (rs34002892, ExAC 0.08%). This variant has been reported as homozygous or in combination with another GNPTAB variant in individuals affected with mucolipidosis (PMID: 16465621, 25606425, 27710913, 24375680, 20880125). This variant is also known as 3665_3666delTC, FS1172X in the literature. ClinVar contains an entry for this variant (Variation ID: 2771). Experimental studies have shown that this frameshift change significantly reduces mRNA and protein expression, abrogates enzyme activity and causes cellular mis-localization of the protein (PMID: 16465621, 24375680). Loss-of-function variants in GNPTAB are known to be pathogenic (PMID: 19617216, 25107912). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000002899 SCV001163704 pathogenic Mucolipidosis type II criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000002900 SCV001194241 pathogenic Pseudo-Hurler polydystrophy 2019-12-24 criteria provided, single submitter clinical testing 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000082192 SCV001247315 pathogenic not provided 2019-03-01 criteria provided, single submitter clinical testing
OMIM RCV000002899 SCV000023057 pathogenic Mucolipidosis type II 2011-09-01 no assertion criteria provided literature only
OMIM RCV000002900 SCV000023058 pathogenic Pseudo-Hurler polydystrophy 2011-09-01 no assertion criteria provided literature only
GeneReviews RCV000002900 SCV000054684 pathologic Pseudo-Hurler polydystrophy 2012-05-10 no assertion criteria provided curation Converted during submission to Pathogenic.
GeneReviews RCV000002899 SCV000055988 pathologic Mucolipidosis type II 2012-05-10 no assertion criteria provided curation Converted during submission to Pathogenic.
Counsyl RCV000002899 SCV001132213 pathogenic Mucolipidosis type II 2016-11-18 no assertion criteria provided clinical testing
Myriad Women's Health, Inc. RCV000002900 SCV001132214 pathogenic Pseudo-Hurler polydystrophy 2016-11-18 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.