ClinVar Miner

Submissions for variant NM_203475.3(PORCN):c.1356del (p.Cys453fs) (rs1602085557)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000853254 SCV000996075 likely pathogenic Focal dermal hypoplasia 2017-09-27 criteria provided, single submitter clinical testing This is a frameshifting variant in exon 15/15 of the PORCN gene. This variant has not been previously reported in the literature to our knowledge. However, small indels, missense, and nonsense variants have been reported in exon 15/15 of the PORCN (which corresponds to the C-terminus of the PORCN protein). This includes a frameshift variant at the adjacent amino acid (PMID: 19586929). Functional studies of terminal truncations of the C-terminus have demonstrated that while a truncated protein is expressed, the altered protein fails to promote WNT3a acetylation (PMID: 24798332). This variant is not reported in the gnomAD database and is thus presumed to be rare. In addition, this gene is highly intolerant of loss-of-function variants. In silico analyses predict the effect of this variant to be damaging. Based on the combined evidence, the p.Cys453AlafsTer8 variant is classified as likely pathogenic.

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