rs558269137

chr1-152312600-CACTG-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 16P and 5B. PVS1 PP5_Very_Strong BS1_Supporting BS2

The NM_002016.2(FLG):c.2282_2285del(p.Ser761CysfsTer36) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0126 in 151,974 control chromosomes in the GnomAD database, including 18 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (18 hom., cov: 29)
  • Exomes 𝑓: 0.020 (396 hom.)
  • Failed GnomAD Quality Control
• Consequence: FLG NM_002016.2 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:29 U:1 O:2
• Conservation: PhyloP100: 0.419

Genes affected

FLG (HGNC:3748): (filaggrin) The protein encoded by this gene is an intermediate filament-associated protein that aggregates keratin intermediate filaments in mammalian epidermis. It is initially synthesized as a polyprotein precursor, profilaggrin (consisting of multiple filaggrin units of 324 aa each), which is localized in keratohyalin granules, and is subsequently proteolytically processed into individual functional filaggrin molecules. Mutations in this gene are associated with ichthyosis vulgaris.[provided by RefSeq, Dec 2009]

FLG-AS1 (HGNC:27913): (cervical cancer associated DHX9 suppressive transcript)

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 104 pathogenic variants in the truncated region.
• PP5: Variant 1-152312600-CACTG-C is Pathogenic according to our data. Variant chr1-152312600-CACTG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 16320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-152312600-CACTG-C is described in Lovd as [Pathogenic]. Variant chr1-152312600-CACTG-C is described in Lovd as [Likely_pathogenic].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0126 (1913/151974) while in subpopulation NFE AF= 0.0219 (1488/67994). AF 95% confidence interval is 0.021. There are 18 homozygotes in gnomad4. There are 865 alleles in male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd at 18 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLG	NM_002016.2	c.2282_2285del	p.Ser761CysfsTer36	frameshift_variant	3/3	ENST00000368799.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLG	ENST00000368799.2	c.2282_2285del	p.Ser761CysfsTer36	frameshift_variant	3/3	1	NM_002016.2	P1
FLG-AS1	ENST00000653548.1	n.390-19978_390-19975del		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0126 AC: 1913 AN: 151856 Hom.: 18 Cov.: 29

Gnomad AFR AF: 0.00378

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00367

Gnomad ASJ AF: 0.00577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00831

Gnomad FIN AF: 0.0132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0219

Gnomad OTH AF: 0.00623

GnomAD3 exomes AF: 0.0129 AC: 3237 AN: 251484 Hom.: 34 AF XY: 0.0128 AC XY: 1738 AN XY: 135914

Gnomad AFR exome AF: 0.00338

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.00754

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00722

Gnomad FIN exome AF: 0.0149

Gnomad NFE exome AF: 0.0213

Gnomad OTH exome AF: 0.0135

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0196 AC: 28705 AN: 1461820 Hom.: 396 AF XY: 0.0191 AC XY: 13885 AN XY: 727210

Gnomad4 AFR exome AF: 0.00335

Gnomad4 AMR exome AF: 0.00186

Gnomad4 ASJ exome AF: 0.00773

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00779

Gnomad4 FIN exome AF: 0.0145

Gnomad4 NFE exome AF: 0.0234

Gnomad4 OTH exome AF: 0.0141

GnomAD4 genome AF: 0.0126 AC: 1913 AN: 151974 Hom.: 18 Cov.: 29 AF XY: 0.0116 AC XY: 865 AN XY: 74280

Gnomad4 AFR AF: 0.00377

Gnomad4 AMR AF: 0.00367

Gnomad4 ASJ AF: 0.00577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00832

Gnomad4 FIN AF: 0.0132

Gnomad4 NFE AF: 0.0219

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.0173 Hom.: 10

Bravo AF: 0.0116

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0182

EpiControl AF: 0.0197

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:29 Uncertain:1 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ichthyosis vulgaris Pathogenic:17

Likely pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 19, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Provincial Medical Genetics Program of British Columbia, University of British Columbia	Jan 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Oct 21, 2021	PVS1, PS4, PM3 -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genomics Laboratory, Washington University in St. Louis	Oct 02, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	May 29, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	May 03, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jan 03, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Feb 17, 2021	ACMG classification criteria: PVS1, PM3 very strong -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 12, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 06, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2006	- -
Pathogenic, criteria provided, single submitter	clinical testing	Wangler Lab, Baylor College of Medicine	-	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Oct 01, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Aug 09, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 01, 2018	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. -

not provided Pathogenic:7

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 08, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 29, 2021	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) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	FLG: PVS1:Strong, PM2, PP1:Moderate, PS4:Moderate -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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. -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

FLG-related disorder Pathogenic:2 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 08, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	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. -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	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. -

Ichthyosis vulgaris;C1853965:Dermatitis, atopic, 2 Pathogenic:1 Uncertain:1

Uncertain significance, flagged submission	clinical testing	Baylor Genetics	Jul 08, 2015	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	Dec 04, 2017	[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]. -

Eczematoid dermatitis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Aug 27, 2019

- -

Dermatitis, atopic, 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing;provider interpretation

Geisinger Autism and Developmental Medicine Institute, Geisinger Health System

Oct 18, 2017

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). -

Dermatitis, atopic, 2, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Oct 01, 2006

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs558269137; hg19: chr1-152285076;