Submissions for variant NM_001367624.2(ZNF469):c.8996G>T (p.Gly2999Val)

gnomAD frequency: 0.00034  dbSNP: rs273585625

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
New York Genome Center	RCV001836730	SCV002097882	uncertain significance	Brittle cornea syndrome 1	2021-02-12	criteria provided, single submitter	clinical testing	The inherited c.8996G>T (p.Gly2999Val) variant identified in the ZNF469 gene substitutes a moderately conserved Glycine for Valine at amino acid 2999/3954 (exon 3/3). This variant is found with low frequency in gnomAD(v3.1) (53 heterozygotes, 0 homozygotes; allele frequency: 3.48e-4) suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Damaging (SIFT; Score:0.017) and Pathogenic (REVEL; score: 0.619) to the function of the canonical transcript. This variant is reported as Pathogenic in ClinVar (VarID:126932), although the evidence used for this classification was not available for review. To our current knowledge the c.8996G>T (p.Gly2999Val) variant has not been reported in affected individuals in the literature. The p.Gly2999 residue is not within a mapped domain of ZNF469 (UniProtKB:Q96JG9). Given the lack of compelling evidence for its pathogenicity, the inherited c.8996G>T(p.Gly2999Val) variant identified in the ZNF469 gene is reported as a Variant of Uncertain Significance.
Ambry Genetics	RCV002371938	SCV002687336	benign	Cardiovascular phenotype	2020-12-09	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317091	SCV004020826	uncertain significance	not specified	2023-06-21	criteria provided, single submitter	clinical testing	Variant summary: ZNF469 c.8996G>T (p.Gly2999Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.6e-05 in 146046 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ZNF469 causing Brittle Cornea Syndrome 1 (9.6e-05 vs 0.0011), allowing no conclusion about variant significance. c.8996G>T has been reported in the literature in an individual affected with keratoconus without strong evidence of causality (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 has been ascertained in the context of this evaluation (PMID: 24895405). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as benign, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV004791268	SCV005411405	uncertain significance	not provided	2023-11-03	criteria provided, single submitter	clinical testing	BS1
Willoughby Group, Queen's University Belfast	RCV000114788	SCV000148683	pathogenic	Keratoconus 1		no assertion criteria provided	not provided	Converted during submission to Pathogenic.