Submissions for variant NM_001329943.3(KIAA0586):c.3003C>A (p.Asn1001Lys)

gnomAD frequency: 0.00018  dbSNP: rs199537542

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000652575	SCV000774445	uncertain significance	Joubert syndrome 23; Short-rib thoracic dysplasia 14 with polydactyly	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 1054 of the KIAA0586 protein (p.Asn1054Lys). This variant is present in population databases (rs199537542, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with KIAA0586-related conditions. ClinVar contains an entry for this variant (Variation ID: 542185). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KIAA0586 protein function with a positive predictive value of 80%. 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.
GeneDx	RCV001584506	SCV001811214	uncertain significance	not provided	2021-02-25	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Genetic Services Laboratory, University of Chicago	RCV001816637	SCV002070141	uncertain significance	not specified	2020-02-21	criteria provided, single submitter	clinical testing	DNA sequence analysis of the KIAA0586 gene demonstrated a sequence change, c.3162C>A, in exon 23 that results in an amino acid change, p.Asn1054Lys. This sequence change does not appear to have been previously described in patients with KIAA0586-related disorders and has been described in the gnomAD database with a low population frequency of 0.030% in non-Finnish European subpopulation (dbSNP rs199537542). The p.Asn1054Lys change affects a moderately conserved amino acid residue located in a domain of the KIAA0586 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Asn1054Lys substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Asn1054Lys change remains unknown at this time.
Fulgent Genetics, Fulgent Genetics	RCV000652575	SCV002775648	uncertain significance	Joubert syndrome 23; Short-rib thoracic dysplasia 14 with polydactyly	2021-09-21	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001584506	SCV004134167	likely benign	not provided	2023-10-01	criteria provided, single submitter	clinical testing	KIAA0586: BP4