Submissions for variant NM_015443.4(KANSL1):c.1421G>A (p.Arg474His) (rs770719196)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000187776	SCV000241373	uncertain significance	not provided	2014-07-16	criteria provided, single submitter	clinical testing	This variant is denoted p.Arg474His (CGT>CAT): c.1421 G>A in exon 3 of the KANSL1 gene (NM_001193466.1). The R474H variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, the R474H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, missense mutations in KANSL1 have not been reported in association with epilepsy. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. With the clinical and molecular information available at this time, the clinical significance of this variant is unknown. The variant is found in INFANT-EPI panel(s).
Invitae	RCV001294648	SCV001483534	uncertain significance	Koolen-de Vries syndrome	2020-10-19	criteria provided, single submitter	clinical testing	Due to the possible presence of a polymorphic segmental duplication, the location of the variant could not be unambiguously resolved. If the variant occurs in the KANSL1 gene, this sequence change replaces arginine with histidine at codon 474 of the KANSL1 protein (p.Arg474His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. The frequency data for this variant in the population databases (ExAC) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This variant has not been reported in the literature in individuals with KANSL1-related conditions. ClinVar contains an entry for this variant (Variation ID: 205788). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). Until the location of this sequence change can be resolved, the clinical significance of this variant remains uncertain. It has been classified as a Variant of Uncertain Significance.