Submissions for variant NM_015443.4(KANSL1):c.2965C>A (p.Pro989Thr)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004702191	SCV005202590	uncertain significance	not specified	2024-07-11	criteria provided, single submitter	clinical testing	Variant summary: KANSL1 c.2965C>A (p.Pro989Thr) results in a non-conservative amino acid change located in the PEHE domain (IPR029332) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250374 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2965C>A in individuals affected with Koolen-De Vries Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005103557	SCV005769428	uncertain significance	Koolen-de Vries syndrome	2024-09-04	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 989 of the KANSL1 protein (p.Pro989Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with KANSL1-related conditions. This missense change has been observed in at least one individual who was not affected with KANSL1-related conditions (internal data). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KANSL1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.