Submissions for variant NM_003482.4(KMT2D):c.15143G>A (p.Arg5048His)

dbSNP: rs886041404

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000376655	SCV000330006	pathogenic	not provided	2021-12-15	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in a patients with Kabuki syndrome in published literature (Miyake et al., 2013; Makrythanasis et al., 2013; Bogershausen et al., 2016); This variant is associated with the following publications: (PMID: 23320472, 23913813, 29304373, 28475860, 30459467, 27302555)
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000505249	SCV000781682	likely pathogenic	Kabuki syndrome 1	2016-11-01	criteria provided, single submitter	clinical testing
Invitae	RCV001220983	SCV001392999	pathogenic	Kabuki syndrome	2022-03-04	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 5048 of the KMT2D protein (p.Arg5048His). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg5048 amino acid residue in KMT2D. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27302555). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KMT2D protein function. ClinVar contains an entry for this variant (Variation ID: 280132). This missense change has been observed in individual(s) with clinical features of Kabuki syndrome (PMID: 23913813, 27302555, 28475860). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency).
Wangler Lab, Baylor College of Medicine	RCV000505249	SCV002577383	pathogenic	Kabuki syndrome 1		criteria provided, single submitter	clinical testing	This missense KMT2D variant at c.15143G>A (p.R5048H) was discovered on exome through the Texome Project (R01HG011795). This variant has been reported in individuals with Kabuki syndrome 1 (PMID: 3913813, 27302555, 28475860, 29304373, 30459467). This variant has not been observed in gnomAD (PM2) and is predicted to be deleterious by multiple computational models (CADD: 31.000) (PP3). The evolutionary conservation of this residue is high. We classify this variant as pathogenic.
Baylor Genetics	RCV000505249	SCV003835254	pathogenic	Kabuki syndrome 1	2022-08-08	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004535247	SCV004116620	pathogenic	KMT2D-related disorder	2023-02-02	criteria provided, single submitter	clinical testing	The KMT2D c.15143G>A variant is predicted to result in the amino acid substitution p.Arg5048His. This is a recurrent de novo variant that is reported to be causative for Kabuki Syndrome (Miyake et al. 2013. PubMed ID: 23913813; Butcher et al. 2017. PubMed ID: 28475860; Aref-Eshghi et al. 2018. PubMed ID: 29304373). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Furthermore, an alternate nucleotide change affecting the same amino acid (p.Arg5048Cys) has also been reported to be causative for Kabuki Syndrome (Hannibal et al. 2011. PubMed ID: 21671394). In summary, the c.15143G>A (p.Arg5048His) variant is interpreted as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000376655	SCV005041026	pathogenic	not provided	2024-04-01	criteria provided, single submitter	clinical testing	KMT2D: PS2:Very Strong, PM2, PM5, PS4:Moderate, PP3
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	RCV000505249	SCV000599269	pathogenic	Kabuki syndrome 1	2016-09-30	no assertion criteria provided	clinical testing