Submissions for variant NM_001367624.2(ZNF469):c.4112dup (p.Pro1373fs)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003123420	SCV003800883	likely pathogenic	Brittle cornea syndrome 1	2023-01-19	criteria provided, single submitter	clinical testing	Variant summary: ZNF469 c.4112dupA (p.Pro1373AlafsX10) located in the last exon (exon 3) 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 been classified as pathogenic by our laboratory and in ClinVar, and is associated with Brittle cornea syndrome in HGMD. The variant was absent in 153746 control chromosomes (gnomAD). To our knowledge, no occurrence of c.4112dupA in individuals affected with Brittle Cornea Syndrome 1 and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003689037	SCV004446725	pathogenic	not provided	2023-08-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Pro1345Alafs*10) in the ZNF469 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 2581 amino acid(s) of the ZNF469 protein. This variant is not present in population databases (gnomAD no frequency). 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: 2429181). This variant disrupts a region of the ZNF469 protein in which other variant(s) (p.Pro3556Glnfs*136) have been determined to be pathogenic (PMID: 32671420). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.