ClinVar Miner

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

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255117 SCV000321674 pathogenic not provided 2021-07-08 criteria provided, single submitter clinical testing Nonsense variant in the N-terminus predicted to result in protein truncation or nonsense-mediated mRNA decay,and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 21039602, 29791750, 22407025, 24920311, 22344438, 28143684, 28407221, 29428354, 31365035, 27535533)
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
Illumina Clinical Services Laboratory,Illumina RCV001270779 SCV001451539 uncertain significance FLG-related disorders 2019-04-30 criteria provided, single submitter clinical testing The FLG c.2476C>T (p.Arg826Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Arg826Ter variant that has been reported in at least six studies in which it is found in a heterozygote state in a total of 11 individuals, including seven with atopic dermatitis (AD), one with atopic dermatitis and ichthyosis vulgaris (IV), two with xerosis, and one with sporadic psoriasis. This variant was also found in a compound heterozygous state in one individual with ichthyosis vulgaris (Zhang et al. 2011; Hu et al. 2012; Polcari et al. 2014; Teye et al. 2017; Margolis DJ 2018; Mathyer et al. 2018). The p.Arg826Ter variant was reported in one of 517 control subjects in a heterozygous state and is reported at a frequency of 0.007629 in the African/African American population of the Genome Aggregation Database. A total of two homozygotes are also reported in this population. Based on the evidence and predicted impact of truncating variants, but higher than expected frequency in population databases, the p.Arg826Ter variant is classified as a variant of uncertain significance for FLG-related disorders.
New York Genome Center RCV000986414 SCV001761151 pathogenic Ichthyosis vulgaris 2020-07-17 criteria provided, single submitter clinical testing The heterozygous p.Arg826Ter stop-gained variant identified in the last exon (3 of 3) of the FLG gene creates a premature translation termination codon and is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. If the mutated mRNA escapes nonsense-mediated decay and gets translated, the resulting truncated proteinwould lack 80% of the normal filaggrin protein (3,235 of the 4,061 residues). This variant has been reportedin multiple individuals affected with atopic dermatitis and ichthyosis vulgaris [PMID: 21039602; PMID: 24920311; PMID: 29791750]. The variant has 0.002186 allele frequency in the gnomAD(v3) database (312 out of 142,732 heterozygous alleles, 2 homozygotes) which is consistent with the observations of high prevalence and milder phenotypic presentations of this disorder. Based on the available evidence, the heterozygous p.Arg826Ter stop-gained variant identified in the FLG gene is assessed as Pathogenic.

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