Submissions for variant NM_001367624.2(ZNF469):c.8350C>T (p.Arg2784Ter)

dbSNP: rs1172315984

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001902073	SCV002127723	pathogenic	not provided	2024-01-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg2756*) in the ZNF469 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1170 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: 1363096). This variant disrupts a region of the ZNF469 protein in which other variant(s) (p.Arg3414Glyfs*59) 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002509711	SCV002819574	likely pathogenic	Brittle cornea syndrome 1	2022-12-15	criteria provided, single submitter	clinical testing	Variant summary: ZNF469 c.8350C>T (p.Arg2784X) is located in exon 3 (i.e. the last exon) and results in a premature termination codon, predicted to remove a large part of the 3925 amino acid long protein, including several zinc finger domains (InterPro). Truncations downstream of this position have been eported in individuals affected with Brittle cornea syndrome (HGMD). The variant was absent in 153844 control chromosomes (gnomAD). To our knowledge, no occurrence of c.8350C>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, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.