Submissions for variant NM_003482.4(KMT2D):c.4358A>G (p.His1453Arg)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV004729282	SCV005333791	likely pathogenic	not provided	2024-03-25	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28884922, 30459467, 21607748)
Labcorp Genetics (formerly Invitae), Labcorp	RCV005103606	SCV005836038	pathogenic	Kabuki syndrome	2024-06-10	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 1453 of the KMT2D protein (p.His1453Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Kabuki syndrome (PMID: 21607748). 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 with a positive predictive value of 95%. This variant disrupts the p.His1453 amino acid residue in KMT2D. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.