ClinVar Miner

Submissions for variant NM_001367624.2(ZNF469):c.10324del (p.Arg3442fs)

gnomAD frequency: 0.00004  dbSNP: rs756543273
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Center for Human Genetics Tuebingen RCV001093036 SCV001249828 uncertain significance not provided 2019-10-01 criteria provided, single submitter clinical testing
GeneDx RCV001093036 SCV001777209 likely pathogenic not provided 2023-09-05 criteria provided, single submitter clinical testing Observed with another frameshift variant on the opposite allele (in trans) in two siblings with mild brittle cornea syndrome (BCS) in published literature (Rolvien et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation, as the last 512 amino acids are replaced with 58 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 32671420, 34368841, 33739556)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002240648 SCV002511625 likely pathogenic Brittle cornea syndrome 1 2022-04-25 criteria provided, single submitter clinical testing Variant summary: ZNF469 c.10324delA (p.Arg3442GlyfsX59) located in the last exon 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. The variant allele was found at a frequency of 4.1e-05 in 144594 control chromosomes. c.10324delA has been reported in the literature as NM_001127464:c.10240delA, p.Arg3414Glyfs*59 in a compound heterozygous genotype with another downstream truncation (c.10751delC, p.Pro3584Glnfs*136, reported as NM_001127464:c.10664delC p.Pro3556Glnfs*136) in at-least two siblings from one family affected with Brittle Cornea Syndrome type 1 (example, Rolvien_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV002276621 SCV002565220 likely pathogenic Ehlers-Danlos syndrome 2021-02-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV002375019 SCV002692231 likely pathogenic Cardiovascular phenotype 2022-01-06 criteria provided, single submitter clinical testing The c.10240delA variant, located in coding exon 2 of the ZNF469 gene, results from a deletion of one nucleotide at nucleotide position 10240, causing a translational frameshift with a predicted alternate stop codon (p.R3414Gfs*59). This alteration occurs at the 3' terminus of theZNF469 gene, is not expected to trigger nonsense-mediated mRNAdecay, and only impacts the last 13% of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). In addition, this alteration has been identified in trans with another ZNF469 frameshift in a family with brittle cornea syndrome (Rolvien T et al. Calcif Tissue Int, 2020 09;107:294-299). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV001093036 SCV003509301 pathogenic not provided 2024-01-09 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg3414Glyfs*59) in the ZNF469 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 512 amino acid(s) of the ZNF469 protein. This variant is present in population databases (rs756543273, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with brittle cornea syndrome (PMID: 32671420). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 872522). This variant disrupts the C-terminus of the ZNF469 protein. Other variant(s) that disrupt this region (p.Pro3556Glnfs*136) have been observed in individuals with ZNF469-related conditions (PMID: 32671420). This suggests that this may be a clinically significant region of the protein. For these reasons, this variant has been classified as Pathogenic.

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