Submissions for variant NM_003482.4(KMT2D):c.1517C>A (p.Pro506Gln)

dbSNP: rs367925817

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001355349	SCV001738893	likely benign	not provided	2021-05-14	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV002070226	SCV002477704	likely benign	Kabuki syndrome	2024-10-30	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355349	SCV001550215	likely benign	not provided		no assertion criteria provided	clinical testing	The KMT2D p.P506Q variant was not identified in the literature nor was it identified in ClinVar. The variant was identified in dbSNP (ID: rs367925817) and in control databases in 14 of 279550 chromosomes at a frequency of 0.00005008, and was observed at the highest frequency in the European (non-Finnish) population in 13 of 127530 chromosomes (freq: 0.0001019) (Genome Aggregation Database March 6, 2019, v2.1.1). This frequency is greater than expected for the rare, autosomal dominant Kabuki syndrome associated with KMT2D variants. The p.P506 residue is conserved in mammals however computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) do not suggest a high likelihood of impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV004758792	SCV005348044	uncertain significance	KMT2D-related disorder	2024-08-26	no assertion criteria provided	clinical testing	The KMT2D c.1517C>A variant is predicted to result in the amino acid substitution p.Pro506Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.010% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.