Submissions for variant NM_002016.2(FLG):c.2476C>T (p.Arg826Ter)

gnomAD frequency: 0.00243  dbSNP: rs115746363

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255117	SCV000321674	pathogenic	not provided	2022-01-27	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 (HGMD); This variant is associated with the following publications: (PMID: 21039602, 29791750, 22407025, 22344438, 28143684, 28407221, 29428354, 31365035, 24920311)
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 Laboratory Services, Illumina	RCV003401213	SCV001451539	pathogenic	FLG-related disorder	2024-09-05	criteria provided, single submitter	clinical testing
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.
Revvity Omics, Revvity	RCV000986414	SCV002023732	pathogenic	Ichthyosis vulgaris	2019-06-17	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000986414	SCV002061845	pathogenic	Ichthyosis vulgaris	2021-06-24	criteria provided, single submitter	clinical testing	PVS1, PS4
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000986414	SCV003807245	pathogenic	Ichthyosis vulgaris	2022-08-19	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 strong, PS4 strong, PM3 moderated
PreventionGenetics, part of Exact Sciences	RCV003401213	SCV004111815	pathogenic	FLG-related disorder	2023-02-24	criteria provided, single submitter	clinical testing	The FLG c.2476C>T variant is predicted to result in premature protein termination (p.Arg826*). This variant has been reported in the heterozygous state in multiple individuals affected by atopic dermatitis, ichthyosis vulgaris, and psoriasis vulgaris, including a control individual later discovered to have a history of asthma (Table 2, Zhang et al. 2010. PubMed ID: 21039602; Table 2, Hu et al. 2012. PubMed ID: 22407025; Table 1, Polcari et al. 2014. PubMed ID: 24920311; Table 1, Mathyer et al. 2018. PubMed ID: 29791750; Table 1, Margolis et al. 2019. PubMed ID: 31365035). This variant is reported in 0.76% of alleles in individuals of African descent, including two homozygotes, in gnomAD (http://gnomad.broadinstitute.org/variant/1-152284886-G-A). Variable expressivity and differing environmental factors may help explain the presence of this loss-of-function FLG variant in individuals in the general population. Nonsense variants in FLG are expected to be pathogenic. This variant is interpreted as pathogenic.
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV000986414	SCV005397410	pathogenic	Ichthyosis vulgaris	2022-04-11	criteria provided, single submitter	clinical testing	This sequence variant is a single nucleotide substitution (C>T) that generates a stop codon at position 826 of the FLG protein. This variant is predicted to generate a non-functiol allele through either the expression of a truncated protein, or a loss of FLG expression due to nonsense mediated decay. This variant has been reported in the literature in several patients with acute dermatitis or ichthyosis vulgaris (PMID: 21428977, 22407025, 29428354, 29791750). This variant is present in control population datasets (gnomAD database 22/282602 alleles or 0.08%). Because haploinsufficiency is a known mechanism of disease for FLG, we consider this variant to be pathogenic. ACMG Criteria: PM3, PVS1
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000986414	SCV005400074	pathogenic	Ichthyosis vulgaris	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with ichthyosis vulgaris (MIM#146700). (I) 0108 - This gene is associated with both recessive and dominant disease. Biallelic truncating variants tend to result in a more severe condition (PMID: 17291859, PMID: 30681730). (I) 0112 - The condition associated with this gene has incomplete penetrance. Heterozygous carriers are more likely to be asymptomatic than individuals with biallelic mutations (PMID: 17291859, PMID: 30681730). (I) 0204 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with at least 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a condition (222 heterozygotes, 2 homozygotes). (SP) 0701 - Other truncating variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in several individuals with FLG-related conditions (ClinVar, PMIDs: 21039602, 24920311, 28143684). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Eurofins Ntd Llc (ga)	RCV000255117	SCV000854944	uncertain significance	not provided	2017-07-31	flagged submission	clinical testing