ClinVar Genomic variation as it relates to human health

The FLG c.7339C>T (p.Arg2447Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. Across a selection of the available literature, the p.Arg2447Ter variant has been identified in a heterozygous state in at least 32 individuals with atopic dermatitis (Weidinger et al. 2008; Greisenegger et al. 2009; Gimalova et al. 2016; González-Tarancon et al. 2020). The p.Arg2447Ter variant was also reported in a heterozygous state in 28 matched population control subjects, and is reported at a frequency of 0.006488 in the European (Finnish) population of the Genome Aggregation Database (version 2.1.1). This allele frequency is high but is consistent with high prevalence and variable severity seen in affected individuals. Based on the evidence, the p.Arg2447Ter variant is classified as pathogenic for FLG-related disorders.

PVS1, PS3

The FLG c.7339C>T (p.Arg2447Ter) variant has been reported in several individuals affected with ichthyosis vulgaris and atopic dermatitis and is reported in a compound heterozygous state with a pathogenic or likely pathogenic variant in at least at least one individual, and in a heterozygous state in over 100 individuals (González-Tarancón R et al., PMID: 31637781; Greisenegger E et al., PMID: 19874431; Gruber R et al., PMID: 19785597; Sandilands A et al., PMID: 17417636; Schuttelaar M et al., PMID: 19839980; Timmerman JG et al., PMID: 26451970; Weidinger S et al., PMID: 18396323). The highest population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 0.65% in the European (non-Finnish) population. This variant has been reported in the ClinVar database as a pathogenic variant by 18 submitters and likely pathogenic by one submitter. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic.

This sequence variant is a single base substitution (C>T) at coding nucleotide 7339 that replaces an arginine codon with a premature termition sigl in exon 3 of 3 of the FLG gene. This variant is expected to truncate the FLG encoded profilaggrin protein, thereby disrupting the filaggrin 7 repeat and elimiting the remaining filaggrin repeats and C termil domain (PMID: 17502856). Loss of the C termil domain prevents processing profilaggrin into filaggrin monomers, generating a loss of function variant (PMID: 17417636, 22071473). This previously reported (ClinVar 50932), well-documented variant is associated with dermatitis and ichthyosis vulgaris (PMID: 17417636, 19874431, 27363669, 31637781, 32066784, 31365035, 33715246). This variant is present in 814/282684 alleles (0.3%), including 1 homozygote, in the gnomAD control population dataset. Protein studies on p.R501Ter/p.R2447Ter compound heterozygous cell lysates showed that profilaggrin was greatly reduced and filaggrin was absent (PMID: 17417636). Given this information, we consider this a pathogenic variant. ACMG Criteria: PS3, PVS1

Recurrent variant that has been reported multiple times in association with ichthyosis vulgaris and atopic dermatitis as one of the more prevalent FLG pathogenic variants among Northern Europeans (Sandilands et al., 2007; Greisenegger et al., 2010; Gimalova et al., 2016); Nonsense variant in the C-terminus predicted to result in protein truncation; 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: 26451970, 17417636, 31365035, 19874431, 19839980, 22951058, 19785597, 22995991, 21377035, 28213896, 27363669, 29068602, 29428354, 29054605, 30665703, 31589614, 33144682)

PVS1, PS2, BS2

ACMG classification criteria: PVS1 very strong, PS4 strong, BS1 strong

The observed stop gained variant c.7339C>T(p.Arg2447Ter) in FLG gene has been reported in heterozygous state in multiple individuals with Ichthyosis vulgaris and atopic dermatitis. This recurrent variant is one of the more prevalent FLG pathogenic variants among Northern Europeans (González-Tarancón R, et al., 2020, Gimalova et al., 2016). The c.7339C>T variant has 0.2% allele frequency in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing (González-Tarancón R, et al., 2020). For these reasons, this variant has been classified as Pathogenic.

FLG: PVS1, PP1, PP4, PS4:Supporting

NM_002016.1:c.7339C>T in the FLG gene has an allele frequency of 0.006 in European(non-Finnish) subpopulation in the gnomAD database.This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. It has been reported multiple times in association with ichthyosis vulgaris and atopic dermatitis as one of the most prevalent FLG pathogenic variants among Northern Europeans (PMID: 17417636; 19874431; 27363669). Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP criteria applied: PVS1; PM2; PS4.

Variant classified as Pathogenic and reported on 09-09-2020 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.