Submissions for variant NM_003482.4(KMT2D):c.15079C>T (p.Arg5027Ter)

dbSNP: rs797045659

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000194362	SCV000247759	pathogenic	Kabuki syndrome 1	2014-07-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000484393	SCV000568829	pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	De novo variant with confirmed parentage in a patient with schizophrenia in published literature, reported using MLL2 as an alternate gene name (PMID: 24776741); Nonsense 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: 21280141, 33314698, 27302555, 34930662, 24776741, 24633898)
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000194362	SCV001190493	pathogenic	Kabuki syndrome 1	2019-12-12	criteria provided, single submitter	research	ACMG codes: PVS1, PS3, PM2, PP5
Ambry Genetics	RCV001266906	SCV001445086	pathogenic	Inborn genetic diseases	2020-02-28	criteria provided, single submitter	clinical testing	The alteration results in a premature stop codon: _x000D_ _x000D_ The c.15079C>T (p.R5027*) alteration, located in coding exon 48 of the KMT2D gene, results from a C to T substitution at nucleotide position 15079. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 5027. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. The alteration is not observed in population databases: _x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the KMT2D c.15079C>T alteration was not observed, with coverage at this position. The alteration has been observed in affected individuals: _x000D_ _x000D_ This alteration has been reported in multiple affected individuals, and has been confirmed to be de novo in multiple cases (Paulussen, 2011; Micale, 2011; Bögershausen, 2016; Cocciadiferro, 2018). Based on the available evidence, this alteration is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001382673	SCV001581569	pathogenic	Kabuki syndrome	2023-06-09	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg5027*) in the KMT2D gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KMT2D are known to be pathogenic (PMID: 22126750). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Kabuki syndrome (PMID: 21280141, 27302555). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 211319). For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000194362	SCV002557299	pathogenic	Kabuki syndrome 1	2022-09-02	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) (I) 0107 - This gene is associated with autosomal dominant disease. (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) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by four clinical laboratories in ClinVar, observed as de novo in one individual in DECIPHER, and identified in at least two individuals with Kabuki syndrome in the literature (PMIDs: 21280141, 32803813). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Baylor Genetics	RCV000194362	SCV005049816	pathogenic	Kabuki syndrome 1	2023-12-12	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000484393	SCV005198604	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing