Submissions for variant NM_001367624.2(ZNF469):c.9919A>G (p.Thr3307Ala)

gnomAD frequency: 0.00072  dbSNP: rs273585627

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000520139	SCV000618246	uncertain significance	not provided	2021-11-04	criteria provided, single submitter	clinical testing	Identified in a patient with isolated keratoconus in the published literature (Lechner et al., 2014); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26582918, 24895405)
CeGaT Center for Human Genetics Tuebingen	RCV000520139	SCV001151059	uncertain significance	not provided	2019-06-01	criteria provided, single submitter	clinical testing
Invitae	RCV000520139	SCV002209643	uncertain significance	not provided	2022-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 3279 of the ZNF469 protein (p.Thr3279Ala). This variant is present in population databases (rs273585627, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with ZNF469-related conditions. ClinVar contains an entry for this variant (Variation ID: 126935). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Ambry Genetics	RCV002381415	SCV002691132	likely benign	Cardiovascular phenotype	2019-05-10	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.
Fulgent Genetics, Fulgent Genetics	RCV002483182	SCV002793859	uncertain significance	Brittle cornea syndrome 1	2022-05-04	criteria provided, single submitter	clinical testing
Willoughby Group, Queen's University Belfast	RCV000114791	SCV000148686	probable-pathogenic	Keratoconus 1		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.