Submissions for variant NM_003482.4(KMT2D):c.6437C>T (p.Pro2146Leu)

gnomAD frequency: 0.00026  dbSNP: rs563981206

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659735	SCV000781583	likely benign	Kabuki syndrome 1	2016-11-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001355052	SCV001819702	likely benign	not provided	2021-02-09	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 30459467)
Genetic Services Laboratory, University of Chicago	RCV001820911	SCV002068178	likely benign	not specified	2021-11-05	criteria provided, single submitter	clinical testing	DNA sequence analysis of the KMT2D gene demonstrated a sequence change, c.6437C>T, in exon 31 that results in an amino acid change, p.Pro2146Leu. This sequence change does not appear to have been previously described in individuals with KMT2D-related disorders and has been described in the gnomAD database with a frequency of 0.029% in the European sub-population (dbSNP rs563981206). The p.Pro2146Leu change affects a moderately conserved amino acid residue located in a domain of the KMT2D protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Pro2146Leu substitution.
Invitae	RCV001850631	SCV002307561	likely benign	Kabuki syndrome	2024-01-26	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001355052	SCV004698597	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	KMT2D: BS1
PreventionGenetics, part of Exact Sciences	RCV004537739	SCV004744072	likely benign	KMT2D-related disorder	2023-12-11	criteria provided, single submitter	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).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355052	SCV001549818	uncertain significance	not provided		no assertion criteria provided	clinical testing	The KMT2D p.Pro2146Leu variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs563981206) and in ClinVar (classified as likely benign by Illumina Clinical Services Laboratory and Centre for Human Genetics for Kabuki syndrome). The variant was identified in 36 of 198952 chromosomes at a frequency of 0.000181 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 3 of 5164 chromosomes (freq: 0.000581), European (non-Finnish) in 26 of 89568 chromosomes (freq: 0.00029), Latino in 6 of 25774 chromosomes (freq: 0.000233) and African in 1 of 20056 chromosomes (freq: 0.00005); it was not observed in the Ashkenazi Jewish, East Asian, European (Finnish) and South Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Pro2146 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001355052	SCV001978657	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001355052	SCV001980279	likely benign	not provided		no assertion criteria provided	clinical testing