Submissions for variant NM_003482.4(KMT2D):c.4395dup (p.Lys1466fs)

dbSNP: rs1555195118

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659718	SCV000781566	likely pathogenic	Kabuki syndrome 1	2016-11-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001233752	SCV001406361	pathogenic	Kabuki syndrome	2019-07-18	criteria provided, single submitter	clinical testing	This variant has been observed in an individual with clinical features of Kabuki syndrome (PMID: 25896430). ClinVar contains an entry for this variant (Variation ID: 547421). For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in KMT2D are known to be pathogenic (PMID: 22126750). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Lys1466Glnfs*25) in the KMT2D gene. It is expected to result in an absent or disrupted protein product.
Laboratory of Medical Genetics, University of Torino	RCV000659718	SCV004171085	pathogenic	Kabuki syndrome 1		criteria provided, single submitter	clinical testing
Medical Genetics Center, Maternal and Child Health Hospital of Hubei Province	RCV000659718	SCV004847178	pathogenic	Kabuki syndrome 1	2023-02-01	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000659718	SCV005086735	pathogenic	Kabuki syndrome 1	2023-12-21	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Kabuki syndrome 1 (MIM#147920). The mechanism for branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome (MIM#620186) is unclear, but is associated with variants in exons 38-39 (PMID: 31949313). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity in individuals with Kabuki syndrome (PMID: 21882399). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic or likely pathogenic by two clinical laboratories in ClinVar, and has been observed in one individual with Kabuki syndrome 1 in the literature (PMID: 25896430). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
GeneDx	RCV004721529	SCV005327130	pathogenic	not provided	2024-02-05	criteria provided, single submitter	clinical testing	Identified in patients with features of KMT2D-related Kabuki syndrome referred for genetic testing at GeneDx and in published literature (PMID: 25896430); Frameshift 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: 25896430)