Submissions for variant NM_015443.4(KANSL1):c.1276C>T (p.Arg426Cys)

gnomAD frequency: 0.00005  dbSNP: rs757224600

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001705010	SCV000241370	likely benign	not provided	2020-11-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001061422	SCV001226165	uncertain significance	Koolen-de Vries syndrome	2021-09-01	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. Variants with ambiguous mapping are still reported relative to the KANSL1 transcript. This sequence change replaces arginine with cysteine at codon 426 of the KANSL1 protein (p.Arg426Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. 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: 205785). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Ambry Genetics	RCV004984732	SCV005603945	likely benign	Inborn genetic diseases	2024-09-27	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
PreventionGenetics, part of Exact Sciences	RCV003895223	SCV004715377	uncertain significance	KANSL1-related disorder	2024-02-23	no assertion criteria provided	clinical testing	The KANSL1 c.1276C>T variant is predicted to result in the amino acid substitution p.Arg426Cys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.