ClinVar Miner

Submissions for variant NM_003482.4(KMT2D):c.12667C>T (p.Gln4223Ter)

dbSNP: rs1555187956
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000578523 SCV000680601 pathogenic not provided 2019-04-22 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 in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27302555, 28973083)
Labcorp Genetics (formerly Invitae), Labcorp RCV001853839 SCV002233986 pathogenic Kabuki syndrome 2025-01-06 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln4223*) in the KMT2D gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KMT2D are known to be pathogenic (PMID: 22126750). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Kabuki syndrome (PMID: 27302555, 28973083, 36474027). ClinVar contains an entry for this variant (Variation ID: 488744). For these reasons, this variant has been classified as Pathogenic.
Daryl Scott Lab, Baylor College of Medicine RCV002245021 SCV002515351 pathogenic Kabuki syndrome 1 2022-02-01 criteria provided, single submitter clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV004545788 SCV004014862 pathogenic KMT2D-related disorder criteria provided, single submitter clinical testing This nonsense variant found in exon 39 of 54 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Loss-of-function variation in KMT2D is an established mechanism of disease (PMID:27302555). This variant has been previously reported as a heterozygous change in patients with Kabuki Syndrome (PMID: 28973083, 27302555). The c.12667C>T (p.Gln4223Ter) variant is absent from the gnomAD population database and thus is presumed to be rare. Based on the available evidence, c.12667C>T (p.Gln4223Ter) is classified as Pathogenic.

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