ClinVar Miner

Submissions for variant NM_002016.2(FLG):c.2476C>T (rs115746363)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255117 SCV000321674 pathogenic not provided 2018-03-28 criteria provided, single submitter clinical testing The R826X pathogenic variant in the FLG gene has been reported previously in association with atopic dermatitis and ichthyosis vulgaris (Zhang et al., 2011; Polcari et al., 2014; Teye et al., 2017). This variant is predicted to cause loss of normal protein function through protein truncation. Consistent with the high incidence and milder phenotype of ichthyosis vulgaris, R826X also was observed in large population cohorts, such as 184/23,970 alleles (0.76%) from individuals of African background, including two homozygous individuals (Lek et al., 2016). We interpret R826X as a pathogenic variant.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000255117 SCV000854944 uncertain significance not provided 2017-07-31 criteria provided, single submitter clinical testing
Mendelics RCV000986414 SCV001135411 likely pathogenic Ichthyosis vulgaris 2019-05-28 criteria provided, single submitter clinical testing
Johns Hopkins Genomics,Johns Hopkins University RCV000986414 SCV001167210 pathogenic Ichthyosis vulgaris 2019-10-04 criteria provided, single submitter clinical testing This nonsense variant is predicted to lead to a premature stop codon (PTC) in the last exon of the gene, likely escaping nonsense-mediated decay and resulting in a truncated protein product. Although the exact function of the C-terminal segment after this PTC is unclear, there are reports of disease-associated nonsense variants located downstream of c.2476C>T. This variant (rs115746363) is present in a large population dataset (gnomAD: 226/282602 total alleles; 0.08%; 2 homozygotes). Mild cases of ichthyosis vulgaris can go undiagnosed or be mistaken for very dry skin, explaining the high frequency in this control population. There are conflicting interpretations of the pathogenicity of this variant in ClinVar. One submitter classified it as pathogenic and one as a variant of uncertain clinical significance. We consider this variant to be pathogenic.
Undiagnosed Diseases Network,NIH RCV001255624 SCV001432156 pathogenic Dermatitis, atopic, 2 2020-01-14 criteria provided, single submitter clinical testing

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