ClinVar Miner

Submissions for variant NM_002016.1(FLG):c.12064A>T (p.Lys4022Ter) (rs146466242)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center RCV000490507 SCV000267320 uncertain significance Ichthyosis vulgaris 2016-03-18 criteria provided, single submitter reference population
GeneDx RCV000114742 SCV000491243 likely pathogenic not provided 2018-06-04 criteria provided, single submitter clinical testing The K4022X variant in the FLG gene is predicted to result in premature truncation of profilaggrin. It is the most 3' loss-of-function variant reported to date, located in the C-terminal incomplete filaggrin repeat. This nonsense variant is considered a potential founder mutation, as it has been reported in both the homozygous and heterozygous state in many individuals of Asian background with IV, atopic dermatitis and psoriasis (Nemoto-Hasebe et al., 2009; Hu et al., 2012; Park et al., 2015). Of note, K4022X was reported as K4021X due to a difference in nomenclature (Nemoto-Hasebe et al., 2009). K4022X has been observed in approximately 2% of alleles from individuals of East Asian background in the 1000 Genomes database, indicating this variant is likely associated with milder clinical features and reduced penetrance. Immunohistochemical staining for filaggrin in epidermis of patients with atopic eczema and K4022X revealed residual, albeit remarkably reduced filaggrin expression compared to controls (Nemoto-Hasebe et al., 2009). This finding is consistent with similar observations made for other loss-of-function variants in the C-terminus of profilaggrin (personal communication with an external gene expert). Therefore, we interpret K4022X as a likely pathogenic variant
OMIM RCV000114742 SCV000148625 uncertain significance not provided 2012-07-01 no assertion criteria provided literature only

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