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

gnomAD frequency: 0.00001  dbSNP: rs273585626

Total submissions: 7

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	2024-06-20	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Identified in a patient with keratoconus in the published literature (PMID: 24895405); 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
Labcorp Genetics (formerly Invitae), Labcorp	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.