Submissions for variant NM_001367624.2(ZNF469):c.6809C>A (p.Ser2270Tyr)

gnomAD frequency: 0.00010  dbSNP: rs273585624

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001804842	SCV002051231	uncertain significance	not specified	2021-12-18	criteria provided, single submitter	clinical testing	Variant summary: ZNF469 c.6809C>A (p.Ser2270Tyr) 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 5.2e-05 in 152738 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6809C>A has been reported in the literature as a VUS with a non-informative genotype in individuals affected with Keratoconus (example, Lechner_2014). These report(s) do 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001854537	SCV002220376	uncertain significance	not provided	2023-11-25	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 2242 of the ZNF469 protein (p.Ser2242Tyr). This variant is present in population databases (rs273585624, gnomAD 0.01%). This missense change has been observed in individual(s) with keratoconus (PMID: 24895405). ClinVar contains an entry for this variant (Variation ID: 126929). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
Ambry Genetics	RCV002362743	SCV002666819	uncertain significance	Cardiovascular phenotype	2023-01-16	criteria provided, single submitter	clinical testing	The p.S2242Y variant (also known as c.6725C>A), located in coding exon 2 of the ZNF469 gene, results from a C to A substitution at nucleotide position 6725. The serine at codon 2242 is replaced by tyrosine, an amino acid with dissimilar properties. This variant 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV001854537	SCV004227626	uncertain significance	not provided	2023-05-12	criteria provided, single submitter	clinical testing	BP4
Willoughby Group, Queen's University Belfast	RCV000114785	SCV000148680	pathogenic	Keratoconus 1		no assertion criteria provided	not provided	Converted during submission to Pathogenic.