ClinVar Miner

Submissions for variant NM_001143992.2(WRAP53):c.492C>A (p.Phe164Leu) (rs281865547)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000439983 SCV000521363 likely pathogenic not provided 2016-10-20 criteria provided, single submitter clinical testing The F164L variant in the WRAP53 gene has been reported previously in an individual with classic dyskeratosis congenita who was compound heterozygous for the F164L variant and another missense variant (R398W) (Zhong et al., 2011). In vitro functional studies using patient-derived cells demonstrated that the compound heterozygous F164L and R398W variants disrupted telomerase trafficking, which prevented telomerase from elognating telomeres (Zhong et al., 2011). The F164L variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The F164L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The F164L variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
OMIM RCV000034152 SCV000045256 pathogenic Dyskeratosis congenita, autosomal recessive, 3 2011-01-01 no assertion criteria provided literature only
GeneReviews RCV000034152 SCV000058089 pathologic Dyskeratosis congenita, autosomal recessive, 3 2012-05-10 no assertion criteria provided curation Converted during submission to Pathogenic.

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