ClinVar Miner

Submissions for variant NM_007129.5(ZIC2):c.1317del (p.Leu440fs)

dbSNP: rs1594292057
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001001046 SCV001158166 pathogenic Holoprosencephaly 5 2019-02-12 criteria provided, single submitter clinical testing The ZIC2 c.1317delG; p.Leu440fs variant, to our knowledge, is not reported in the medical literature or gene specific databases. This variant is also absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, ZIC2 loss-of-function is a known mechanism of disease, and truncating variants downstream of the p.Leu440fs variant have been reported in individuals with holoprosencephaly (Roessler 2009). Based on available information, this variant is considered to be pathogenic. References: Roessler E et al. The full spectrum of holoprosencephaly-associated mutations within the ZIC2 gene in humans predicts loss-of-function as the predominant disease mechanism. Hum Mutat. 2009 Apr;30(4):E541-54.
Invitae RCV001001046 SCV004506275 pathogenic Holoprosencephaly 5 2023-04-20 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 811286). This frameshift has been observed in individual(s) with holoprosencephaly (Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change results in a frameshift in the ZIC2 gene (p.Leu440Trpfs*115). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 93 amino acid(s) of the ZIC2 protein and extend the protein by 21 additional amino acid residues.

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