ClinVar Miner

Submissions for variant NM_017739.3(POMGNT1):c.1539+1G>A (rs138642840)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000153760 SCV000329689 pathogenic not provided 2018-08-20 criteria provided, single submitter clinical testing The c.1539+1G>A splice site variant in the POMGNT1 gene has been previously reported in both the homozygous and compound heterozygous state in association with muscle-eye-brain disease (MEB) and is considered to be a common Finnish founder mutation (Diesen et al., 2004). This pathogenic variant destroys the canonical splice donor site in intron 17, and functional studies demonstrate that c.1539+1G>A causes read-through of intronic sequences, resulting in introduction of a premature termination codon (Yoshida et al., 2001). Therefore, c.1539+1G>A is interpreted as a pathogenic variant.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000153760 SCV000331069 pathogenic not provided 2016-08-25 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000323217 SCV000357985 pathogenic POMGNT1-Related Disorders 2017-04-27 criteria provided, single submitter clinical testing The POMGNT1 c.1539+1G>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. Across a selection of available literature, the c.1539+1G>A variant has been identified in at least 35 individuals with POMGNT1-related disorders, including in a homozygous state in 25 individuals and in a compound heterozygous state in six individuals and five fetuses (Yoshida et al. 2001; Taniguchi et al. 2003; Deisen et al. 2004; Vajsar et al. 2006; Hehr et al. 2007; Bouchet et al. 2007; Godfrey et al. 2007; Teber et al. 2008; Devisme et al. 2012; Amir et al. 2016). The c.1539+1G>A variant was reported in three of 1000 control alleles in a heterozygous state and at a frequency of 0.00240 in the European (Finnish) population of the Exome Aggregation Consortium. RT-PCR analysis confirmed that the variant disrupts splicing resulting in the skipping of exon 17 and premature truncation of the protein (Yoshida et al. 2001). Functional studies using targeted expression in HEK293 cells or fibroblasts from patients demonstrated that the POMGNT1 enzyme activity was significantly reduced (Yoshida et al. 2001; Vajsar et al. 2006). Based on the collective evidence, the c.1539+1G>A variant is classified as pathogenic for POMGNT1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Genetic Services Laboratory,University of Chicago RCV000501155 SCV000596517 pathogenic Congenital muscular alpha-dystroglycanopathy with brain and eye anomalies 2015-12-10 criteria provided, single submitter clinical testing
Invitae RCV000648199 SCV000770013 pathogenic Limb-girdle muscular dystrophy-dystroglycanopathy, type C3; Congenital muscular dystrophy-dystroglycanopathy with mental retardation, type B3 2019-11-21 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 17 of the POMGNT1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs138642840, ExAC 0.2%). This variant has been reported in the homozygous or compound heterozygous state in individuals affected with muscle-eye-brain disease and congenital muscular dystrophy (PMID: 11709191, 23326386). This variant is also known as IVS17+1G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 56582). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in POMGNT1 are known to be pathogenic (PMID: 19299310). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000763345 SCV000894030 pathogenic Muscle eye brain disease; Limb-girdle muscular dystrophy-dystroglycanopathy, type C3; Congenital muscular dystrophy-dystroglycanopathy with mental retardation, type B3; Retinitis pigmentosa 76 2018-10-31 criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV001030748 SCV001193937 pathogenic Congenital muscular dystrophy-dystroglycanopathy with mental retardation, type B3 2019-12-09 criteria provided, single submitter clinical testing NM_017739.3(POMGNT1):c.1539+1G>A is classified as pathogenic in the context of POMGNT-related disorders. Sources cited for classification include the following: PMID 15466003 and 11709191. Classification of NM_017739.3(POMGNT1):c.1539+1G>A is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function 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 RCV000153760 SCV001248088 pathogenic not provided 2018-10-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001196668 SCV001367299 pathogenic Macrocephalus; Palmar pits; Basal cell carcinoma 2019-09-16 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP4. This variant was detected in heterozygous state.
Institute of Human Genetics, University of Leipzig Medical Center RCV000049995 SCV001440556 uncertain significance Muscle eye brain disease 2019-01-01 criteria provided, single submitter clinical testing
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000049995 SCV000082404 probable-pathogenic Muscle eye brain disease no assertion criteria provided not provided Converted during submission to Likely pathogenic.
Counsyl RCV000983990 SCV000678144 pathogenic Retinitis pigmentosa 76 2015-06-14 no assertion criteria provided clinical testing

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