Submissions for variant NM_001367624.2(ZNF469):c.1483C>T (p.Pro495Ser)

gnomAD frequency: 0.00073  dbSNP: rs202205643

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000728426	SCV000582270	uncertain significance	not provided	2024-08-26	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29228253)
Eurofins Ntd Llc (ga)	RCV000728426	SCV000856002	uncertain significance	not provided	2017-08-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764084	SCV000895048	uncertain significance	Brittle cornea syndrome 1	2024-01-16	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000728426	SCV001248609	likely benign	not provided	2024-09-01	criteria provided, single submitter	clinical testing	ZNF469: BP4
Labcorp Genetics (formerly Invitae), Labcorp	RCV000728426	SCV002140073	uncertain significance	not provided	2022-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 495 of the ZNF469 protein (p.Pro495Ser). This variant is present in population databases (rs202205643, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with keratoconus (PMID: 29228253). ClinVar contains an entry for this variant (Variation ID: 429651). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0". The serine 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.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002279267	SCV002565279	uncertain significance	Ehlers-Danlos syndrome	2020-04-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002395196	SCV002700432	likely benign	Cardiovascular phenotype	2021-07-06	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	RCV003419830	SCV004109588	uncertain significance	ZNF469-related disorder	2023-05-15	criteria provided, single submitter	clinical testing	The ZNF469 c.1483C>T variant is predicted to result in the amino acid substitution p.Pro495Ser. This variant was reported in an affected individual and in a control from a keratoconus case-control study (Lucas et al. 2017. PubMed ID: 29228253). This variant is reported in 0.13% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-88495361-C-T). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Breakthrough Genomics, Breakthrough Genomics	RCV000728426	SCV005193582	uncertain significance	not provided		criteria provided, single submitter	not provided
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000728426	SCV001808773	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000728426	SCV001964587	likely benign	not provided		no assertion criteria provided	clinical testing