ClinVar Miner

Submissions for variant NM_001367624.2(ZNF469):c.9131C>T (p.Thr3044Met)

gnomAD frequency: 0.00001  dbSNP: rs273585626
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000269420 SCV000334365 uncertain significance not provided 2016-09-06 criteria provided, single submitter clinical testing
GeneDx RCV000269420 SCV001767764 uncertain significance not provided 2021-04-02 criteria provided, single submitter clinical testing Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 126933; Landrum et al., 2016); Identified in a patient with keratoconus in the published literature (Lechner et al., 2014); This variant is associated with the following publications: (PMID: 24895405)
Ambry Genetics RCV002371939 SCV002688078 uncertain significance Cardiovascular phenotype 2019-08-13 criteria provided, single submitter clinical testing The p.T3016M variant (also known as c.9047C>T), located in coding exon 2 of the ZNF469 gene, results from a C to T substitution at nucleotide position 9047. The threonine at codon 3016 is replaced by methionine, an amino acid with similar properties. This variant was identified in an individual with keratoconus (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.
Fulgent Genetics, Fulgent Genetics RCV002490769 SCV002783871 uncertain significance Brittle cornea syndrome 1 2022-03-04 criteria provided, single submitter clinical testing
Invitae RCV000269420 SCV003443661 uncertain significance not provided 2022-06-17 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 3016 of the ZNF469 protein (p.Thr3016Met). This variant is present in population databases (rs273585626, 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: 126933). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003155076 SCV003844313 uncertain significance not specified 2023-02-28 criteria provided, single submitter clinical testing Variant summary: ZNF469 c.9131C>T (p.Thr3044Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.9e-05 in 152840 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9131C>T has been reported in the literature in individuals affected with Keratoconus (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. Five ClinVar submitters have assessed the variant since 2014: all five classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Willoughby Group, Queen's University Belfast RCV000114789 SCV000148684 pathogenic Keratoconus 1 no assertion criteria provided not provided Converted during submission to Pathogenic.

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