Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Diagnostics Services |
RCV000856681 | SCV000998943 | uncertain significance | Global developmental delay; Cerebellar atrophy; Kleefstra syndrome 2 | 2019-08-29 | criteria provided, single submitter | clinical testing | This variant is not present in publicly available databases like 1000 Genomes, Exome Variant Server (EVS), Exome Aggregation Consortium (ExAC), Genome Aggregation Database (gnomAD) and dbSNP. The variant is also not present in our in-house exome database. In-silico pathogenicity prediction programs like Mutation Taster2, CADD, InterVar etc. predicted this variant as likely disease causing. The variant has been classified as uncertain significance considering the clinical phenotype of the patient. Also validation of this variant was not performed however recommended to the patient family due to the presence of other highly homologus genomic regions. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001193315 | SCV001362066 | likely pathogenic | Kleefstra syndrome 2 | 2021-01-20 | criteria provided, single submitter | clinical testing | Variant summary: KMT2C c.2961C>G (p.Tyr987X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 204330 control chromosomes (gnomAD); of note, the region surrounding the variant is highly affected by pseudogene interference, therefore NGS data for this region (from studies or databases) should be evaluated with caution. The variant, c.2961C>G, has not been reported in the literature in individuals affected with Kleefstra Syndrome 2, but has been reported in patients affected with various types of tumors, most likely as a somatic occurrence (e.g. Yap_2018, Adam_2019, Hirotsu_2020, Peng_2019). These reports do not provide unequivocal conclusions about association of the variant with Kleefstra Syndrome 2. A recent study reported that loss-of-function variants in the KMT2C gene are firmly associated with dominant developmental disorders (PMID 29276005). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Neuberg Centre For Genomic Medicine, |
RCV001193315 | SCV005438725 | likely pathogenic | Kleefstra syndrome 2 | criteria provided, single submitter | clinical testing | The stop gained c.2961C>G p.Tyr987Ter variant in KMT2C has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Tyr987Ter variant is absent not in any individuals in gnomAD exomes database. This variant has been submitted to the ClinVar database as Uncertain significance / Likely pathogenic. The nucleotide change c.2961C>G in KMT2C is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Computational evidence MutationTaster - disease causing predict a damaging effect on protein structure and function for this variant. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Likely Pathogenic. |