ClinVar Miner

Submissions for variant NM_001003722.2(GLE1):c.433-10A>G

gnomAD frequency: 0.00082  dbSNP: rs386833693
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000824239 SCV000965128 pathogenic not provided 2023-11-17 criteria provided, single submitter clinical testing This sequence change falls in intron 3 of the GLE1 gene. It does not directly change the encoded amino acid sequence of the GLE1 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been observed in individuals with lethal congenital contracture syndrome (PMID: 7770128, 16892327, 18204449). It is commonly reported in individuals of Finnish ancestry (PMID: 7770128, 16892327, 18204449). This variant is also known as Fin(Major). ClinVar contains an entry for this variant (Variation ID: 6462). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects GLE1 function (PMID: 24243016). 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.
OMIM RCV000006833 SCV000027029 pathogenic Lethal congenital contracture syndrome 1 2008-02-01 no assertion criteria provided literature only
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000049654 SCV000082061 pathogenic Lethal arthrogryposis-anterior horn cell disease syndrome no assertion criteria provided not provided Converted during submission to Pathogenic.
Reproductive Health Research and Development, BGI Genomics RCV000006833 SCV001142404 pathogenic Lethal congenital contracture syndrome 1 2020-01-06 no assertion criteria provided curation NG_012073.1(NM_001003722.1):c.433-10A>G in the GLE1 gene has an allele frequency of 0.012 in European (Finnish) subpopulation in the gnomAD database. This variant has been observed in individuals affected with lethal congenital contracture syndrome (PMID: 18204449) and is a founder variant in the Finnish population (PMID: 16892327; 7770128). Experimental studies have shown that this intronic change leads to aberrant mRNA splicing, resulting in a GLE1 protein with defective oligomerization (PMID: 24243016). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PS4; PS3; PP4.
Natera, Inc. RCV001276648 SCV001463110 pathogenic Lethal congenital contractural syndrome Finnish type 2020-09-16 no assertion criteria provided clinical testing

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