Submissions for variant NM_001197104.2(KMT2A):c.10835+1G>C

gnomAD frequency: 0.00004  dbSNP: rs141515578

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001756461	SCV001985239	uncertain significance	not provided	2024-08-30	criteria provided, single submitter	clinical testing	Identified in a patient with Wiedemann-Steiner syndrome and in a patient with autism spectrum disorder in published literature (PMID: 33783954, 36368308); Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 33783954, 36368308)
Genetic Services Laboratory, University of Chicago	RCV001821976	SCV002065838	uncertain significance	not specified	2021-06-23	criteria provided, single submitter	clinical testing	DNA sequence analysis of the KMT2A gene demonstrated a sequence change in the canonical splice donor site of intron 28, c.10835+1G>C. This sequence change has been described in the gnomAD database with a frequency of 0.0044% in the non-Finnish European subpopulation (dbSNP rs141515578). This sequence change is predicted to affect mRNA splicing and is likely to result in an absent or truncated protein. Although this sequence change has not been previously reported, a different nucleotide change at this position, c.10835+1G>A, has been identified in individuals with a variety of phenotypes. One individual had language delay, left occipital spikes on electroencephalogram, and isolated agenesis of the corpus callosum (PMID 32094338). In a different family, twin boys diagnosed with Wiedemann-Steiner syndrome both carried the c.10835+1G>A variant as well as their mother who reportedly had mild intellectual disability and dysmorphic facial features (PMID: 28623346). Experimental studies demonstrated that this variant (c.10835+1G>A) resulted in skipping of exon 28 and an in-frame deletion of 81 base pairs which was confirmed by analyses on cDNA derived from the patients' blood. Due to insufficient evidences and the lack of functional studies, the clinical significance of the c.10835+1G>C change remains unknown at this time.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001756461	SCV002127274	pathogenic	not provided	2024-12-31	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 28 of the KMT2A gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs141515578, gnomAD 0.004%). Disruption of this splice site has been observed in individuals with clinical features of Wiedemann-Steiner syndrome (PMID: 28623346, 33783954; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1302962). Studies have shown that disruption of this splice site results in skipping of exon 28, but is expected to preserve the integrity of the reading-frame (PMID: 28623346). For these reasons, this variant has been classified as Pathogenic.