Submissions for variant NM_001367624.2(ZNF469):c.7931G>A (p.Arg2644Gln)

gnomAD frequency: 0.00010  dbSNP: rs281865152

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002408615	SCV002669371	uncertain significance	Cardiovascular phenotype	2021-07-12	criteria provided, single submitter	clinical testing	The p.R2616Q variant (also known as c.7847G>A), located in coding exon 2 of the ZNF469 gene, results from a G to A substitution at nucleotide position 7847. The arginine at codon 2616 is replaced by glutamine, an amino acid with highly similar properties. This variant has been detected in a keratoconus cohort (Lechner J et al. Hum Mol Genet, 2014 Oct;23:5527-35). This amino acid position is not well conserved in available vertebrate species, and glutamine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002513946	SCV003009263	uncertain significance	not provided	2022-06-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 2616 of the ZNF469 protein (p.Arg2616Gln). This variant is present in population databases (rs281865152, gnomAD 0.1%). This missense change has been observed in individual(s) with clinical features of ZNF469-related conditions (PMID: 24895405). ClinVar contains an entry for this variant (Variation ID: 126946). 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 glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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.
GeneDx	RCV002513946	SCV003805460	uncertain significance	not provided	2023-02-16	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24895405)
Willoughby Group, Queen's University Belfast	RCV000114802	SCV000148697	probable-pathogenic	Keratoconus 1		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.