Submissions for variant NM_001367624.2(ZNF469):c.2297G>A (p.Arg766Gln)

gnomAD frequency: 0.00111  dbSNP: rs144492145

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000725898	SCV000340337	uncertain significance	not provided	2016-04-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000325707	SCV000491427	uncertain significance	not specified	2016-12-12	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the ZNF469 gene. The R766Q variant has been reported inone European patient with keratoconus and classified as a polymorphism (Lechner et al., 2014). The R766Q variant was not observed in approximately 2,200 individuals of European andAfrican American ancestry in the NHLBI Exome Sequencing Project (average read depth: 5.0), and was not observedwith any significant frequency in the Exome Aggregation Consortium (ExAC). The R766Q variant is asemi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ insome properties. However, this substitution occurs at a position that is not conserved across species, and in silicoanalysis predicts this variant likely does not alter the protein structure/function.
CeGaT Center for Human Genetics Tuebingen	RCV000725898	SCV001151042	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	ZNF469: BP4, BS2
Labcorp Genetics (formerly Invitae), Labcorp	RCV000725898	SCV002434210	benign	not provided	2025-01-30	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002278300	SCV002565303	likely benign	Ehlers-Danlos syndrome	2022-03-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002450821	SCV002738127	likely benign	Cardiovascular phenotype	2019-10-21	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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	RCV000325707	SCV005883328	likely benign	not specified	2024-12-17	criteria provided, single submitter	clinical testing	Variant summary: ZNF469 c.2297G>A (p.Arg766Gln) results in a conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 1544706 control chromosomes, predominantly at a frequency of 0.0018 within the Non-Finnish European subpopulation in the gnomAD database (v4), including 2 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in ZNF469 causing Brittle cornea syndrome 1, allowing no conclusion about variant significance. To our knowledge, no occurrence of c.2297G>A in individuals affected with Brittle cornea syndrome 1 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 286776). Based on the evidence outlined above, the variant was classified as likely benign.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000725898	SCV001807537	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000725898	SCV001975414	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003909987	SCV004722163	likely benign	ZNF469-related disorder	2022-12-20	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).