Submissions for variant NM_003482.4(KMT2D):c.15061C>T (p.Arg5021Ter)

dbSNP: rs587783695

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000146174	SCV000193405	pathogenic	Kabuki syndrome 1	2013-08-14	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000790679	SCV000230778	pathogenic	not provided	2014-01-02	criteria provided, single submitter	clinical testing
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000146174	SCV000781680	likely pathogenic	Kabuki syndrome 1	2016-11-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000146174	SCV001138714	pathogenic	Kabuki syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000790679	SCV001803960	pathogenic	not provided	2019-06-24	criteria provided, single submitter	clinical testing	Identified in multiple individuals with a clinical diagnosis of Kabuki syndrome (Banka et al., 2012; Cocciadiferro et al., 2018); Identified in the mosaic state in an individual with dysmorphic facial features, borderline intellectual disability, and emotional dysregulation (Lepri et al., 2017); 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: 29283410, 29536651, 30107592, 22126750)
CeGaT Center for Human Genetics Tuebingen	RCV000790679	SCV004704319	pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	KMT2D: PVS1, PM2, PS4:Supporting
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000146174	SCV004800983	pathogenic	Kabuki syndrome 1	2024-03-13	criteria provided, single submitter	curation	The heterozygous p.Arg5021Ter variant in KMT2D was identified by our study in one individual with Brown syndrome, developmental delay, sensorineural hearing loss, gastroesophageal reflux, pes planus, and cerebellar malformations and white matter anomalies on brain MRI, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Engle lab (https://kirbyneuro.org/EngleLab/). Trio genome analysis showed this variant to be de novo. We believe this is a possible phenotype expansion for Kabuki syndrome 1. The p.Arg5021Ter variant in KMT2D has been previously reported in 5 unrelated individuals with Kabuki syndrome 1 (PMID: 29304373, PMID: 29283410, PMID: 30107592, PMID: 29536651, PMID: 22126750). The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. This variant has also been reported in ClinVar (Variation ID: 158734) and has been interpreted as pathogenic or likely pathogenic by multiple submitters. This variant was absent from large population studies. This nonsense variant leads to a premature termination codon at position 5021, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the KMT2D gene is an established disease mechanism in Kabuki syndrome 1. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Kabuki syndrome 1. ACMG/AMP Criteria applied: PVS1, PS2_Supporting, PS4, PM2_Supporting (Richards 2015).
Autoinflammatory diseases unit, CHU de Montpellier	RCV000146174	SCV001438200	pathogenic	Kabuki syndrome 1	2016-09-20	no assertion criteria provided	clinical testing