Submissions for variant NM_003482.4(KMT2D):c.12844C>T (p.Arg4282Ter)

dbSNP: rs1057517992

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413702	SCV000491329	pathogenic	not provided	2023-09-11	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 (gnomAD); This variant is associated with the following publications: (PMID: 24633898, 28973083)
Eurofins Ntd Llc (ga)	RCV000413702	SCV000706936	pathogenic	not provided	2017-03-14	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000594502	SCV000807274	pathogenic	Kabuki syndrome 1	2017-09-01	criteria provided, single submitter	clinical testing	This nonsense mutation is categorized as deleterious according to ACMG guidelines (PMID:18414213) and was found once in our laboratory de novo in a newborn male with Shone's complex, cleft palate, sacral dimple, redundant nuchal skin, preauricular pits, dysmorphisms, 2-vessel cord, small kidneys, port wine stain, hypoplastic nails
MGZ Medical Genetics Center	RCV000594502	SCV002579962	pathogenic	Kabuki syndrome 1	2022-05-02	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004530513	SCV004115042	pathogenic	KMT2D-related disorder	2023-05-02	criteria provided, single submitter	clinical testing	The KMT2D c.12844C>T variant is predicted to result in premature protein termination (p.Arg4282*). This variant has been reported as a de novo pathogenic variant for Kabuki Syndrome (Micale et al. 2014. PubMed ID: 24633898; eTable 3, Meng et al. 2017. PubMed ID: 28973083). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in KMT2D are expected to be pathogenic. This variant is interpreted as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003588627	SCV004295032	pathogenic	Kabuki syndrome	2024-01-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg4282*) 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 Kabuki syndrome (PMID: 24633898, 27530205). ClinVar contains an entry for this variant (Variation ID: 372805). For these reasons, this variant has been classified as Pathogenic.
Daryl Scott Lab, Baylor College of Medicine	RCV000594502	SCV005871320	pathogenic	Kabuki syndrome 1	2024-01-01	criteria provided, single submitter	clinical testing	PVS1, PS2, PS3, PM2
Xiao lab, Department of Pathology, Memorial Sloan Kettering Cancer Center	RCV000984092	SCV001132061	likely pathogenic	Multiple myeloma	2019-08-31	no assertion criteria provided	clinical testing
Clinical Genomics Laboratory, Stanford Medicine	RCV000594502	SCV001427023	pathogenic	Kabuki syndrome 1	2018-12-07	no assertion criteria provided	clinical testing	The p.Arg4282* variant in the KMT2D has been identified in at least 4 individuals with Kabuki syndrome, which occurred de novo in 3 individuals (Micale et al., 2014; Schott et al., 2016; Meng et al., 2017; Cocciadiferro et al., 2018). The p.Arg4282* variant was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org). This variant leads to a premature stop codon in exon 39 of 54 coding exons, and is therefore predicted to result in nonsense-mediated decay resulting in a truncated or absent protein. Heterozygous loss of function is an established mechanism of disease for the KMT2D gene. These data were assesed using ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Arg4282* variant as pathogenic for autosomal dominant Kabuki syndrome based on the information above. [ACMG evidence codes used: PVS1, PS2, PM2]