Submissions for variant NM_003482.4(KMT2D):c.3392C>T (p.Pro1131Leu)

dbSNP: rs201623566

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mendelics	RCV000988841	SCV001138730	uncertain significance	Kabuki syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000988841	SCV001367189	uncertain significance	Kabuki syndrome 1	2019-03-01	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: BP4.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000988841	SCV001472834	uncertain significance	Kabuki syndrome 1	2021-09-01	criteria provided, single submitter	clinical testing	The KMT2D c.3392C>T; p.Pro1131Leu variant (rs201623566) is reported in the literature in individuals affected with Kabuki Syndrome (Micale 2014 and Faundes 2019). This variant is found in the Finnish European population with an allele frequency of 0.7% (identified on 164/24,936 alleles, including 1 homozygote) in the Genome Aggregation Database. The proline at codon 1131 is weakly conserved, and computational analyses (SIFT:damaging, PolyPhen-2:benign) predict conflicting effects of this variant on protein structure/function. However, given the lack of clinical and functional data, the significance of the p.Pro1131Leu variant is uncertain at this time. Pathogenic variants in KMT2D are associated with autosomal dominant Kabuki syndrome 1 (MIM: 147920). References: Micale et al. Molecular analysis, pathogenic mechanisms, and readthrough therapy on a large cohort of Kabuki syndrome patients. Hum Mutat. 2014 Jul;35(7):841-50. Faundes et al. A comparative analysis of KMT2D missense variants in Kabuki syndrome, cancers and the general population. J Hum Genet. 2019 Feb;64(2):161-170.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001521913	SCV001731333	benign	Kabuki syndrome	2024-01-26	criteria provided, single submitter	clinical testing
GeneDx	RCV001594848	SCV001828088	benign	not provided	2020-06-24	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24728327, 30459467, 24633898)
CeGaT Center for Human Genetics Tuebingen	RCV001594848	SCV005093435	benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	KMT2D: PP2, BP4, BS1, BS2
ITMI	RCV000121381	SCV000085565	not provided	not specified	2013-09-19	no assertion provided	reference population
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001594848	SCV001928715	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001594848	SCV001975426	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004530008	SCV004750636	likely benign	KMT2D-related disorder	2019-03-25	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).