Submissions for variant NM_012193.4(FZD4):c.1350T>A (p.Cys450Ter)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV003318028	SCV004021353	likely pathogenic	not provided	2023-01-13	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation, as the last 88 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 35328049)
Labcorp Genetics (formerly Invitae), Labcorp	RCV003318028	SCV005751993	pathogenic	not provided	2024-04-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Cys450*) in the FZD4 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 88 amino acid(s) of the FZD4 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with familial exudative vitreoretinopathy (PMID: 35328049, 35951321). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2573692). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects FZD4 function (PMID: 35951321). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts a region of the FZD4 protein in which other variant(s) (p.Gln505*) have been determined to be pathogenic (PMID: 15223780). 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.