Submissions for variant NM_001367624.2(ZNF469):c.10700G>A (p.Gly3567Glu)

gnomAD frequency: 0.00185  dbSNP: rs199610834

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000585441	SCV000345955	uncertain significance	not provided	2016-09-15	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000381105	SCV000399447	uncertain significance	Brittle cornea syndrome 1	2016-06-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000585441	SCV000525873	likely benign	not provided	2022-04-12	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000585441	SCV000692879	likely benign	not provided	2024-06-01	criteria provided, single submitter	clinical testing	ZNF469: BP4, BS2
Invitae	RCV000585441	SCV002484821	likely benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002278326	SCV002565239	likely benign	Ehlers-Danlos syndrome	2020-12-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002402006	SCV002713043	benign	Cardiovascular phenotype	2021-05-13	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	RCV003226277	SCV003922831	likely benign	not specified	2023-03-09	criteria provided, single submitter	clinical testing	Variant summary: ZNF469 c.10700G>A (p.Gly3567Glu) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.001 in 153112 control chromosomes (with 1 homozygote), predominantly at a frequency of 0.0017 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately two fold of the estimated maximal expected allele frequency for a pathogenic variant in ZNF469 causing Brittle Cornea Syndrome 1 phenotype (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.10700G>A in individuals affected with Brittle Cornea Syndrome 1 and no experimental evidence demonstrating its impact on protein function have been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=2) and likely benign/benign (n=5). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003920176	SCV004733726	likely benign	ZNF469-related disorder	2022-07-15	criteria provided, single submitter	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).