Submissions for variant NM_001367624.2(ZNF469):c.290C>T (p.Pro97Leu)

gnomAD frequency: 0.00004  dbSNP: rs273585617

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002433603	SCV002750951	uncertain significance	Cardiovascular phenotype	2021-04-27	criteria provided, single submitter	clinical testing	The p.P97L variant (also known as c.290C>T), located in coding exon 1 of the ZNF469 gene, results from a C to T substitution at nucleotide position 290. The proline at codon 97 is replaced by leucine, an amino acid with similar properties. This alteration has been reported in a keratoconus cohort (Lechner J et al. Hum Mol Genet, 2014 Oct;23:5527-35). This amino acid position is poorly conserved in available 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	RCV002514568	SCV003443635	uncertain significance	not provided	2022-07-15	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 97 of the ZNF469 protein (p.Pro97Leu). This variant is present in population databases (rs273585617, gnomAD 0.01%). 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: 126923). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0". The leucine 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155075	SCV003844263	uncertain significance	not specified	2024-03-21	criteria provided, single submitter	clinical testing	Variant summary: ZNF469 c.290C>T (p.Pro97Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 138202 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.290C>T has been reported in the literature in at least one individual affected with keratoconus (e.g. Lechner_2014). This report does not provide unequivocal conclusions about association of the variant with Brittle Cornea Syndrome 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 24895405). ClinVar contains an entry for this variant (Variation ID: 126923). Based on the evidence outlined above, the variant was classified as uncertain significance.
Willoughby Group, Queen's University Belfast	RCV000114779	SCV000148674	pathogenic	Keratoconus 1		no assertion criteria provided	not provided	Converted during submission to Pathogenic.