Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Center for Human Genetics, |
RCV000659684 | SCV000781530 | uncertain significance | Kabuki syndrome 1 | 2016-11-01 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV001854633 | SCV002175149 | uncertain significance | Kabuki syndrome 2 | 2023-12-11 | criteria provided, single submitter | clinical testing | This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 220 of the KDM6A protein (p.Lys220Asn). This variant is present in population databases (rs587778423, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with KDM6A-related conditions. ClinVar contains an entry for this variant (Variation ID: 134601). 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 not expected to disrupt KDM6A protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Victorian Clinical Genetics Services, |
RCV001854633 | SCV002557198 | uncertain significance | Kabuki syndrome 2 | 2022-02-02 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Kabuki syndrome 2 (MIM#300867). (I) 0110 - This gene is associated with X-linked dominant disease. Heterozygous females can be mildly affected and may have random or skewed X-inactivation (PMID:27302555, OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from lysine to asparagine. (I) 0253 - This variant is hemizygous. (I) 0302 - Variant is present in gnomAD (v2, v3) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes, 1 hemizygote). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated TPR repeat domain (NCBI, UniProt). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported as a VUS and observed in a healthy cohort (ClinVar). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |
| Ambry Genetics | RCV002517592 | SCV003693236 | uncertain significance | Inborn genetic diseases | 2021-08-26 | criteria provided, single submitter | clinical testing | The c.660A>T (p.K220N) alteration is located in exon 9 (coding exon 9) of the KDM6A gene. This alteration results from a A to T substitution at nucleotide position 660, causing the lysine (K) at amino acid position 220 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |
| ITMI | RCV000121291 | SCV000085462 | not provided | not specified | 2013-09-19 | no assertion provided | reference population |