Submissions for variant NM_001367624.2(ZNF469):c.2063C>A (p.Thr688Asn)

gnomAD frequency: 0.00004  dbSNP: rs281865146

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001553702	SCV001774669	uncertain significance	not specified	2021-08-02	criteria provided, single submitter	clinical testing	Variant summary: ZNF469 c.2063C>A (p.Thr688Asn) results in a non-conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 149178 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2063C>A has been reported in the literature in an individual with keratoconus phenotype who carried the variant in the heterozygous state (Lechner_2014). It has been hypothesized that heterozygous variants in ZNF469 may predispose to the development of keratoconus, however this variant has not, to our knowledge, been reported in individuals in the homozygous or compound heterozygous state and has not been reported in patients with brittle cornea syndrome. 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. 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	RCV002514570	SCV003443618	uncertain significance	not provided	2022-07-16	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 688 of the ZNF469 protein (p.Thr688Asn). This variant is present in population databases (rs281865146, gnomAD 0.004%). This missense change has been observed in individual(s) with ZNF469-related conditions (PMID: 24895405). ClinVar contains an entry for this variant (Variation ID: 126938). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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.
Willoughby Group, Queen's University Belfast	RCV000114794	SCV000148689	pathogenic	Keratoconus 1		no assertion criteria provided	not provided	Converted during submission to Pathogenic.