Submissions for variant NM_001367624.2(ZNF469):c.7079C>T (p.Pro2360Leu)

gnomAD frequency: 0.00188  dbSNP: rs76389306

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000384522	SCV000399387	uncertain significance	Brittle cornea syndrome 1	2016-06-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000428390	SCV000532156	likely benign	not specified	2017-10-20	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
CeGaT Center for Human Genetics Tuebingen	RCV001531246	SCV001746264	likely benign	not provided	2024-05-01	criteria provided, single submitter	clinical testing	ZNF469: BP4, BS2
Labcorp Genetics (formerly Invitae), Labcorp	RCV001531246	SCV002239111	likely benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000428390	SCV002500528	likely benign	not specified	2022-03-02	criteria provided, single submitter	clinical testing	Variant summary: ZNF469 c.7079C>T (p.Pro2360Leu) results in a non-conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0019 in 151402 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 1 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 benign. c.7079C>T has been reported in the literature in individuals with inherited eye diseases without evidence for causality (Lucas_2017 and Li_2021). These reports do 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. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=1) and likely benign (n=2) . Based on the evidence outlined above, the variant was classified as likely benign.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002278466	SCV002565394	likely benign	Ehlers-Danlos syndrome	2022-06-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002365384	SCV002665174	likely benign	Cardiovascular phenotype	2022-08-29	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.
PreventionGenetics, part of Exact Sciences	RCV003922358	SCV004750230	likely benign	ZNF469-related disorder	2022-07-10	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).