Submissions for variant NM_003482.4(KMT2D):c.6595del (p.Tyr2199fs)

dbSNP: rs398123753

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000146222	SCV000193462	pathogenic	Kabuki syndrome 1	2013-09-25	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000790813	SCV000229436	pathogenic	not provided	2016-01-04	criteria provided, single submitter	clinical testing
Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine	RCV000146222	SCV000583538	pathogenic	Kabuki syndrome 1		criteria provided, single submitter	research
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000146222	SCV000781585	pathogenic	Kabuki syndrome 1	2016-11-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001040506	SCV001204085	pathogenic	Kabuki syndrome	2024-03-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr2199Ilefs*65) 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 diagnosis or suspicion of Kabuki syndrome (PMID: 20711175, 21607748, 22126750, 23320472, 25755104, 25972376, 27302555, 27620904, 28256057, 28884922, 29255178). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 94239). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000790813	SCV002497597	pathogenic	not provided	2022-03-01	criteria provided, single submitter	clinical testing	KMT2D: PVS1, PS2, PM2
GeneDx	RCV000790813	SCV002504245	pathogenic	not provided	2022-01-10	criteria provided, single submitter	clinical testing	Frameshift 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 (gnomAD); This variant is associated with the following publications: (PMID: 27302555, 20711175, 28256057, 25972376, 29255178, 31727177, 31633846, 34232366)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000146222	SCV004020925	pathogenic	Kabuki syndrome 1	2023-06-27	criteria provided, single submitter	clinical testing	Variant summary: MLL2 c.6595delT (p.Tyr2199IlefsX65) 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. The variant was absent in 151426 control chromosomes (gnomAD). c.6595delT has been reported in the literature in individuals affected with Kabuki Syndrome (e.g., DiCandia_2022). These data suggest the variant is likely to be associated with disease. The following publication was ascertained in the context of this evaluation (PMID: 34232366). Seven submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n = 6) or likely pathogenic (n = 1). Based on the evidence outlined above, the variant was classified as pathogenic.
Genetics and Molecular Pathology, SA Pathology	RCV000146222	SCV004175643	pathogenic	Kabuki syndrome 1	2022-09-20	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV005222741	SCV005871466	pathogenic	Kabuki syndrome 1; Choanal atresia-athelia-hypothyroidism-delayed puberty-short stature syndrome		criteria provided, single submitter	clinical testing	PM2_Supporting+PVS1+PS4+PM6_VeryStrong+PP4
Shaikh Laboratory, University of Colorado	RCV000146222	SCV000207397	likely pathogenic	Kabuki syndrome 1	2015-02-04	no assertion criteria provided	research
Autoinflammatory diseases unit, CHU de Montpellier	RCV000146222	SCV001438217	pathogenic	Kabuki syndrome 1	2018-02-15	no assertion criteria provided	clinical testing