Submissions for variant NM_003482.4(KMT2D):c.12889T>C (p.Ser4297Pro)

gnomAD frequency: 0.00031  dbSNP: rs370243498

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001002641	SCV001160626	uncertain significance	Kabuki syndrome 1	2019-06-27	criteria provided, single submitter	clinical testing	The KMT2D c.12889T>C; p.Ser4297Pro variant (rs370243498) is reported in the literature in at least one individual with suspected Kabuki syndrome (Aref-Eshghi 2018). This variant is found in the general population with an overall allele frequency of 0.021% (52/246492 alleles) in the Genome Aggregation Database. The serine at codon 4297 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, given the lack of clinical and functional data, the significance of the p.Ser4297Pro variant is uncertain at this time. References: Aref-Eshghi E et al. Genomic DNA Methylation Signatures Enable Concurrent Diagnosis and Clinical Genetic Variant Classification in Neurodevelopmental Syndromes. Am J Hum Genet. 2018 Jan 4;102(1):156-174.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001410364	SCV001612410	likely benign	Kabuki syndrome	2025-01-23	criteria provided, single submitter	clinical testing
GeneDx	RCV001683722	SCV001904506	benign	not provided	2020-06-10	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 30459467, 28933623)
Ambry Genetics	RCV002549185	SCV003684588	likely benign	Inborn genetic diseases	2022-07-05	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
CeGaT Center for Human Genetics Tuebingen	RCV001683722	SCV004130715	likely benign	not provided	2022-05-01	criteria provided, single submitter	clinical testing	KMT2D: PP2, BS2
PreventionGenetics, part of Exact Sciences	RCV004545010	SCV004764869	likely benign	KMT2D-related disorder	2023-06-23	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).