Submissions for variant NM_001367624.2(ZNF469):c.9268C>T (p.Arg3090Ter)

dbSNP: rs764139968

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000175661	SCV000227194	pathogenic	not provided	2015-06-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002228785	SCV002511626	likely pathogenic	Brittle cornea syndrome 1	2022-04-14	criteria provided, single submitter	clinical testing	Variant summary: ZNF469 c.9268C>T (p.Arg3090X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have not been classified as pathogenic by our laboratory but are reported in association with Brittle Cornea Syndrome in the HGMD database. The variant was absent in 149116 control chromosomes. To our knowledge, no occurrence of c.9268C>T in individuals affected with Brittle Cornea Syndrome 1 and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000175661	SCV004483570	pathogenic	not provided	2023-06-05	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the ZNF469 protein in which other variant(s) (p.Gln3178Argfs*23) have been determined to be pathogenic (PMID: 18452888; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 195115). This variant has not been reported in the literature in individuals affected with ZNF469-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg3062*) in the ZNF469 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 864 amino acid(s) of the ZNF469 protein.