ClinVar Miner

Submissions for variant NM_020751.3(COG6):c.1535T>G (p.Leu512Ter)

gnomAD frequency: 0.00003  dbSNP: rs1292534396
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000498315 SCV000589796 likely pathogenic not provided 2021-07-10 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27535533)
Fulgent Genetics, Fulgent Genetics RCV000763333 SCV000894010 pathogenic COG6-ongenital disorder of glycosylation; Hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome 2018-10-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001824809 SCV002074146 likely pathogenic COG6-ongenital disorder of glycosylation 2022-01-08 criteria provided, single submitter clinical testing Variant summary: COG6 c.1535T>G (p.Leu512X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have not been classified as pathogenic by our laboratory but have been reported with an associated phenotype of Congenital disorder of glycosylation in the HGMD database (example, c.1843C>T, p.Gln615*). The variant allele was found at a frequency of 8e-06 in 250414 control chromosomes. To our knowledge, no occurrence of c.1535T>G in individuals affected with Congenital Disorder Of Glycosylation Type 2L and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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