ClinVar Miner

Submissions for variant NM_001033044.4(GLUL):c.3G>A (p.Met1Ile)

dbSNP: rs2101936697
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001755207 SCV001996073 uncertain significance not provided 2020-01-06 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); Initiation codon variant in a gene for which loss-of-function is not a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge
Undiagnosed Diseases Network, NIH RCV001788835 SCV002030292 uncertain significance Glutamine related condition 2021-09-07 criteria provided, single submitter clinical testing
Women's and Children's Health, University of Otago RCV003883701 SCV004177219 likely pathogenic Glutamine synthetase stabilization disorder 2023-12-01 no assertion criteria provided clinical testing
OMIM RCV004526144 SCV005038961 pathogenic Developmental and epileptic encephalopathy 116 2024-04-30 no assertion criteria provided literature only
PreventionGenetics, part of Exact Sciences RCV004731172 SCV005339609 pathogenic GLUL-related disorder 2024-08-16 no assertion criteria provided clinical testing The GLUL c.3G>A variant is predicted to disrupt the translation initiation site (p.Met1?). This variant was reported to have occurred de novo in an individual with developmental and epileptic encephalopathy, hypotonia, global developmental delay, and brain abnormalities including hypomyelination (Jones et al. 2024. PubMed ID: 38579670). Other variants that impact the start codon have been reported to have occurred de novo in multiple individuals with similar phenotypes (Supplementary Table 1, Kaplanis. 2020. PubMed ID: 33057194; Table S5, Esterhuizen et al. 2023. PubMed ID: 36480001; Jones et al. 2024. PubMed ID: 38579670). Based on functional studies, variants that impact the start codon result in utilization of a downstream methionine (p.Met18) as the initiation codon, and result in a glutamate synthetase enzyme that is insensitive to glutamine-mediated degradation (Jones et al. 2024. PubMed ID: 38579670). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.

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