Submissions for variant NM_003482.4(KMT2D):c.15535C>T (p.Arg5179Cys)

dbSNP: rs794727688

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000178651	SCV000331792	pathogenic	not provided	2016-07-11	criteria provided, single submitter	clinical testing
GeneDx	RCV000178651	SCV000491328	pathogenic	not provided	2016-10-31	criteria provided, single submitter	clinical testing	The R5179C pathogenic variant in the KMT2D gene has been reported previously in association with Kabuki syndrome (Dentici et al., 2015; Bogershausen et al., 2016). This variant was not observed in approximately 6300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R5179C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, a missense variant in the same amino acid residue (R5179H) has been reported in association with Kabuki syndrome (Ng et al., 2010), supporting the functional importance of this region of the protein. We interpret R5179C as a pathogenic variant, consistent with the global developmental delay, intrauterine growth retardation, hypotonia, and strabismus.
Ambry Genetics	RCV000623497	SCV000742836	pathogenic	Inborn genetic diseases	2017-08-24	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001852217	SCV002238813	pathogenic	Kabuki syndrome	2024-03-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 5179 of the KMT2D protein (p.Arg5179Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Kabuki syndrome (PMID: 27302555, 29536651). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 197586). 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.Arg5179 amino acid residue in KMT2D. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20711175, 23913813, 25755104, 27302555). 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.