Submissions for variant NM_002016.2(FLG):c.2282_2285del (p.Ser761fs)

dbSNP: rs558269137

Total submissions: 34

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000017714	SCV000297112	pathogenic	Ichthyosis vulgaris	2018-05-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000256057	SCV000321673	pathogenic	not provided	2021-10-29	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Results in a functional null allele as no processed filaggrin can be biochemically detected in patients with this variant (Smith et al., 2006); This variant is associated with the following publications: (PMID: 23947670, 27462351, 25314673, 19839980, 19501237, 19538357, 19733298, 20426775, 20573035, 21365004, 21377035, 22403702, 21777221, 21564328, 23166590, 23039796, 23343419, 24920311, 25390410, 27363669, 26451970, 27279822, 27535533, 24251354, 27959697, 28866311, 16444271, 28213896, 29068602, 29431110, 29444371, 29054605, 28164424, 31365035, 30739909, 25747786, 31130284, 31980526, 31216405, 32371413, 17164798)
Baylor Genetics	RCV000017714	SCV000328722	pathogenic	Ichthyosis vulgaris	2024-01-13	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000017714	SCV000712217	pathogenic	Ichthyosis vulgaris	2018-08-01	criteria provided, single submitter	clinical testing	The p.Ser761CysfsX36 variant in FLG is a well-established pathogenic variant ass ociated with the development of ichthyosis vulgaris and atopic dermatitis. FLG-a ssociated skin conditions have reduced penetrance and seasonal variation of the phenotype (Smith 2006). This variant is common in the general population and has been identified in 1.3% (3639/277136) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs138381300). Loss of function of FLG is an established disease mechanism for ichthyosis vulgaris and related dermatological disorders. Individuals who carry heterozygous loss-of-fun ction FLG variants tend to have a mild phenotype or can be asymptomatic, while i ndividuals who carry homozygous or compound heterozygous loss-of-function varian ts in FLG tend to have moderate or severe presentations of ichthyosis vulgaris ( Smith 2006). Patients homozygous for this variant had absent filaggrin by bioche mical analysis (Smith 2006). In summary, this variant meets our criteria to be c lassified as pathogenic for ichthyosis vulgaris. ACMG/AMP Criteria applied: PVS1 , PS4.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System	RCV000678372	SCV000804438	pathogenic	Dermatitis, atopic, 2	2017-10-18	criteria provided, single submitter	provider interpretation	This 10 year old male with autism spectrum disorder, intellectual disability, large stature, macrocephaly, eczema, and seizures was found to carry a maternally inherited variant in the FLG gene. His mother reportedly does not have eczema, but reduced penetrance has been previously noted. The c.2282_2285delCAGT variant is present in 2.0% of individuals of non-Finnish European background in ExAC. This variant is a functional null allele as no processed filaggrin can be biochemically detected in patients with this variant (Smith et al., 2006).
Eurofins Ntd Llc (ga)	RCV000256057	SCV000854988	pathogenic	not provided	2018-08-08	criteria provided, single submitter	clinical testing
Mendelics	RCV000017714	SCV001135412	likely pathogenic	Ichthyosis vulgaris	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000256057	SCV001245946	pathogenic	not provided	2024-04-01	criteria provided, single submitter	clinical testing	FLG: PVS1:Strong, PM2, PP1:Moderate, PS4:Moderate
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	RCV000191085	SCV001423652	pathogenic	Dermatitis, atopic, 2; Ichthyosis vulgaris	2017-12-04	criteria provided, single submitter	clinical testing	[ACMG/AMP: PVS1, PS4, PM3, PP1] This alteration is a null variant in a gene where LOF is a known mechanism of disease [PVS1], has a prevalence that is significantly increased compared with controls (RR/OR > 5; CI does not include 1.0) [PS4], is detected in trans with a known pathogenic variant [PM3], has been shown to cosegregate with disease in multiple affected family members [PP1].
Johns Hopkins Genomics, Johns Hopkins University	RCV000017714	SCV001438366	pathogenic	Ichthyosis vulgaris	2020-10-01	criteria provided, single submitter	clinical testing	This FLG variant (rs558269137) is present in a large population dataset (gnomAD: 3716/282796 total alleles; 1.3%; 39 homozygotes) and has an entry in ClinVar. It is considered one of the more common disease-associated variants in individuals with European ancestry. This frameshift deletion is predicted to lead to a premature stop codon (PTC) in the last exon of the gene. Processed filaggrin could not be biochemically detected in individuals that are homozygous for this variant. Not everyone with a disease-associated variant in FLG will develop atopic dermatitis, consistent with an increased frequency of this variant in controls from the European population (2.2%)7. We consider c.2282_2285del to be pathogenic.
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV001270060	SCV001448813	pathogenic	Eczematoid dermatitis	2019-08-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000017714	SCV001478713	pathogenic	Ichthyosis vulgaris	2021-01-12	criteria provided, single submitter	clinical testing	Variant summary: FLG c.2282_2285delCAGT (p.Ser761CysfsX36) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by other laboratories. The variant allele was found at a frequency of 0.013 in 251484 control chromosomes in the gnomAD database, including 34 homozygotes. c.2282_2285delCAGT has been reported in the literature in multiple individuals affected with Ichthyosis Vulgaris or atopic dermatitis (e.g. Sandilands_2007, Seidl-Philipp_2019). One case-control study showed that this variant is strongly associated with atopic dermatitis (OR=8.94, P=7.8 x 10^-7). These data indicate that the variant is very likely to be associated with disease. Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Pathogenic/likely pathogenic n=10, VUS n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000017714	SCV002061663	pathogenic	Ichthyosis vulgaris	2021-10-21	criteria provided, single submitter	clinical testing	PVS1, PS4, PM3
New York Genome Center	RCV000017714	SCV002098025	pathogenic	Ichthyosis vulgaris	2020-05-29	criteria provided, single submitter	clinical testing
Provincial Medical Genetics Program of British Columbia, University of British Columbia	RCV000017714	SCV002320786	pathogenic	Ichthyosis vulgaris	2022-01-01	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000017714	SCV002512381	pathogenic	Ichthyosis vulgaris	2021-02-17	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1, PM3 very strong
Wangler Lab, Baylor College of Medicine	RCV000017714	SCV002577614	pathogenic	Ichthyosis vulgaris		criteria provided, single submitter	clinical testing	This frameshift FLG variant at c.2282_2285del (p.S761Cfs*36) was discovered on exome through the Texome Project (R01HG011795). This is a frameshift variant that is located in exon 3 of 3 (PVS1). This variant was previously reported in individuals with Ichthyosis vulgaris (PMID: 23947670, 27279822). This variant has been described in heterozygous, compound heterozygous and homozygous states in affected individuals and is considered to have an incomplete penetrance and variable expression (PM3). This variant has been observed in gnomAD with a frequency of 1.310%. We classify this variant as pathogenic.
MGZ Medical Genetics Center	RCV000017714	SCV002580653	pathogenic	Ichthyosis vulgaris	2022-01-03	criteria provided, single submitter	clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000017714	SCV002764705	pathogenic	Ichthyosis vulgaris	2022-08-09	criteria provided, single submitter	clinical testing
3billion	RCV000017714	SCV003841493	pathogenic	Ichthyosis vulgaris	2023-02-23	criteria provided, single submitter	clinical testing	The variant is observed as homozygous in at least two unrelated individuals/adults in the gnomAD v.2.1.1 dataset. This variant was predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000016320 / PMID: 16444271). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Illumina Laboratory Services, Illumina	RCV000017714	SCV004014698	pathogenic	Ichthyosis vulgaris	2023-05-19	criteria provided, single submitter	clinical testing	The FLG c.2282_2285delCAGT (p.Ser761CysfsTer36) variant, also commonly referred to as c.2282del4 or p.S761fs, is a recurrent variant that causes a shift in the protein reading frame that is predicted to result in premature termination of the protein. This variant occurs in the last exon of the gene and may escape nonsense-mediated mRNA decay. This variant has been reported in over 100 individuals in the heterozygous state, and in over 25 individuals in the homozygous or compound heterozygous state, all of whom presented with phenotypes consistent with ichthyosis vulgaris including atopic dermatitis, allergic sensitizations, eczema, and/or fissure on hands or fingers (PMID: 16444271; PMID: 16550169; PMID: 16810297; PMID: 16815158; PMID: 19874431; PMID: 23343419; PMID: 27279822; PMID: 27363669; PMID: 31637781). The p.Ser761CysfsTer36 variant has been shown to segregate in a semidominant manner with ichthyosis vulgaris such that individuals who have biallelic loss of function variants display more pronounced phenotypes compared to heterozygotes (PMID: 16444271). Additionally, the p.Ser761CysfsTer36 variant has been reported to confer a significant increase in the risk of ichthyosis vulgaris features among heterozygous individuals with odds ratios ranging from 1.93 and 24.15 (PMID: 19874431; PMID: 23343419; PMID: 27279822; PMID: 27363669). The estimated overall frequency of this variant in individuals with phenotypes consistent with ichthyosis vulgaris ranges from 0.9% to 20.85% whereas its frequency in control populations ranges from 0.5% to 3.48% (PMID: 31637781). It is most common in those of northern European ancestry and relatively uncommon in those of southern European, Asian and African ancestries. The highest frequency of this variant in the Genome Aggregation Database is 0.021610 in the European (non-Finnish) population, which includes 33 homozygotes (version 2.1.1). This frequency is high but is consistent with disease prevalence estimates, variable severity, incomplete penetrance, and presumed under-ascertainment of mildly affected individuals. Based on the collective evidence, the p.Ser761CysfsTer36 variant is classified as pathogenic for ichthyosis vulgaris.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV003398531	SCV004046166	pathogenic	FLG-related disorder		criteria provided, single submitter	clinical testing	This variant has been reported in association with ichthyosis vulgaris, eczema, asthma, and allergic sensitizations in the heterozygous, homozygous, and compound heterozygous state (PMID: 16444271, 16550169, 17030239, 19501237, 16815158, 19538357, 19733298, 21377035, 21777221, 22403702, 23039796, 23343419). It is present in the gnomAD population database at a frequency of 1.3% (3716/282796) and is observed in the homozygous state in 39 individuals. Functional studies have confirmed this variant leads to loss of filaggrin protein production (PMID: 16444271). Based on the available evidence, c.2282_2285del (p.Ser761CysfsTer36) is classified as Pathogenic.
Clinical Genomics Laboratory, Washington University in St. Louis	RCV000017714	SCV004177069	pathogenic	Ichthyosis vulgaris	2023-10-02	criteria provided, single submitter	clinical testing	The FLG c.2282_2285del (p.Ser761CysfsTer36) variant, also known as c.2282del4 or p.S761fs, has been described in the homozygous and compound heterozygous state in several individuals affected with icthyosis vulgaris and this variant has been associated with an increased risk for eczema (OR 1.93-24.15; Gimalova GF et al., PMID: 27363669; Greisenegger E et al., PMID: 19874431; Thyssen JP et al., PMID: 23343419; Wo≈∫niak M et al., PMID: 2727982). Individuals that were homozygous for this variant had significantly reduced filaggrin by immunohistochemistry (Smith FJ et al., PMID: 16444271). The highest population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 2.1% in the European (non-Finnish) population which is consistent with the reported incidence of low penetrance ichthyosis vulgaris in heterozygotes. This variant causes a frameshift by deleting two nucleotides, leading to a premature termination codon; however, because this occurs in the last exon, this is not predicted to lead to nonsense mediated decay. The terminal exon is large and several pathogenic FLG variants have been described downstream of this variant. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000256057	SCV005090764	pathogenic	not provided	2024-07-31	criteria provided, single submitter	clinical testing
Centre for Clinical Genetics and Genomic Diagnostics, Zealand University Hospital	RCV000256057	SCV005328430	likely pathogenic	not provided	2024-06-26	criteria provided, single submitter	clinical testing
OMIM	RCV000017714	SCV000037991	pathogenic	Ichthyosis vulgaris	2006-10-01	no assertion criteria provided	literature only
OMIM	RCV000017715	SCV000037992	risk factor	Dermatitis, atopic, 2, susceptibility to	2006-10-01	no assertion criteria provided	literature only
Baylor Genetics	RCV000191085	SCV000245481	uncertain significance	Dermatitis, atopic, 2; Ichthyosis vulgaris	2015-07-08	flagged submission	clinical testing	This variant has been previously reported as disease-causing and was found nine times in our laboratory in individuals with skin features: in a 20-year-old female with ichthyosis, inherited from her father with ichthyosis; in an 18-year-old female with eczema; a 2-year-old male with dry palms and mild ichthyosis; in a 9-year-old male with eczema and dry skin; a 10-year-old female with eczema; a 5-year-old female with eczema; a 55-year-old male with severe eczema; a 1-year-old male with skin rash on scalp, face, and back; a 6-year-old female with psoriasis & carotenoderma. However, it has been seen a total of 161 times, with the remaining cases not specifically mentioning significant skin findings.
GenomeConnect, ClinGen	RCV003398531	SCV000840291	not provided	FLG-related disorder		no assertion provided	phenotyping only	The variant was identified in multiple GenomeConnect participants. The variant was interpreted as Pathogenic and reported, most recently, on 08-31-2021 by Lab or GTR ID 26957. The variant was also interpreted as pathogenic by Lab or GTR ID 1006 on 07-28-2014. 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000256057	SCV001552929	pathogenic	not provided		no assertion criteria provided	clinical testing	The FLG p.S761Cfs*36 variant is known to contribute to eczema (atopic dermatitis) and ichthyosis vulgaris with phenotype variability and reduced penetrance (Visser_2013_PMID:23039796; Marenholz_2016_PMID:17030239; Weidinger_2006_PMID:16815158; Thyssen_2012_PMID:21777221; Poninska_2011_PMID:21365004; Smith_2006_PMID:16444271; Palmer_2006_PMID:16550169). The variant was identified in dbSNP (ID: rs558269137) and ClinVar (classified as pathogenic by Laboratory for Molecular Medicine, GeneDx and seven other submitters; as likely pathogenic by Mendelics; and as uncertain significance by Baylor Genetics). The variant was identified in control databases in 3716 of 282796 chromosomes (39 homozygous) at a frequency of 0.01314, and was observed at the highest frequency in the European (non-Finnish) population in 2791 of 129164 chromosomes (freq: 0.02161) (Genome Aggregation Database March 6, 2019, v2.1.1). The c.2282_2285del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 761 and leads to a premature stop codon 36 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the FLG gene are an established mechanism of disease in ichthyosis vulgaris and is the type of variant expected to cause the disorder. Additionally, functional analysis has demonstrated that this variant results in loss of filaggrin production and impaired epidermal barrier formation (Smith_2006_PMID:16444271). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000256057	SCV001743042	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000256057	SCV001806900	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000256057	SCV001973529	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003398531	SCV004104648	likely pathogenic	FLG-related disorder	2024-09-17	no assertion criteria provided	clinical testing	The FLG c.2282_2285delCAGT variant is predicted to result in a frameshift and premature protein termination (p.Ser761Cysfs*36). This variant has been reported in the heterozygous, compound heterozygous, and homozygous states in patients with ichthyosis vulgaris and atopic dermatitis (Smith et al. 2006. PubMed ID: 16444271; Palmer et al. 2006. PubMed ID: 16550169; Wozniak et al. 2016. PubMed ID: 27279822). Heterozygotes display a milder phenotype with incomplete penetrance. Functional studies indicate that this sequence variant results in complete absence of the functionally important filaggrin peptide (Smith et al. 2006. PubMed ID: 16444271). This variant is reported in 2.2% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in FLG are expected to be pathogenic. This variant is interpreted as likely pathogenic, with incomplete penetrance and variable expressivity.