ClinVar Miner

Submissions for variant NM_017739.4(POMGNT1):c.1769G>A (p.Trp590Ter)

gnomAD frequency: 0.00003  dbSNP: rs386834019
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000050000 SCV000221091 likely pathogenic Muscle eye brain disease 2015-01-28 criteria provided, single submitter literature only
Invitae RCV000820354 SCV000961063 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2O; Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3 2024-01-03 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp590*) in the POMGNT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in POMGNT1 are known to be pathogenic (PMID: 19299310, 20816175, 21447391, 26908613, 27391550). This variant is present in population databases (rs386834019, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with muscle-eye-brain (MEB) disease (PMID: 15466003, 21361872). ClinVar contains an entry for this variant (Variation ID: 56587). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Genomics England Pilot Project, Genomics England RCV001542522 SCV001760037 pathogenic Retinitis pigmentosa 76 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002496725 SCV002812296 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2O; Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3; Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3; Retinitis pigmentosa 76 2022-02-14 criteria provided, single submitter clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV002514265 SCV003761151 pathogenic Muscular dystrophy-dystroglycanopathy 2023-01-24 criteria provided, single submitter curation The p.Trp590Ter variant in POMGNT1 has been reported in one individual with muscular dystrophy-dystroglycanopathy (PMID: 15466003), and has been identified in 0.002% (2/128260) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs386834019). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#:56587) and has been interpreted as pathogenic by Invitae, Genomics England, and Natera, Inc, probable-pathogenic by the Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) and likely pathogenic by Counsyl. In vitro functional studies provide some evidence that the p.Arg590Ter variant may impact protein function, as reflected by reduced catalytic activity in an in vitro enzymatic activity assay (PMID: 21361872). However, these types of assays may not accurately represent biological function. This nonsense variant leads to a premature termination codon at position 590, which is predicted to lead to a truncated or absent protein. Loss of function of the POMGNT1 gene is an established disease mechanism in autosomal recessive POMGNT1-associated muscular dystrophy-dystroglycanopathy. In summary, this variant meets criteria to be classified as pathogenic for POMGNT1-associated muscular dystrophy-dystroglycanopathy. ACMG/AMP Criteria applied: PVS1, PM2_supporting, PS3_Supporting (Richards 2015).
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000050000 SCV000082409 probable-pathogenic Muscle eye brain disease no assertion criteria provided not provided Converted during submission to Likely pathogenic.
Natera, Inc. RCV000050000 SCV002089588 pathogenic Muscle eye brain disease 2021-08-17 no assertion criteria provided clinical testing

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