VCV000016320.71 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(36)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 16320 Accession: VCV000016320.71

Type and length

Microsatellite, 4 bp

Location

Cytogenetic: 1q21.3 1: 152312601-152312604 (GRCh38) [ NCBI UCSC ] 1: 152285077-152285080 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Aug 13, 2015	Nov 24, 2024	Jul 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_002016.2:c.2282_2285del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002007.1:p.Ser761fs	frameshift
NM_002016.2:c.2282_2285delCAGT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_002016.1:c.2282_2285delCAGT
NC_000001.11:g.152312601ACTG[1]
NC_000001.10:g.152285077ACTG[1]
NG_016190.1:g.17596CAGT[1]
LRG_1028:g.17596CAGT[1]

... more HGVS ... less HGVS

Protein change

S761fs

Other names

Canonical SPDI

NC_000001.11:152312600:ACTGACTG:ACTG

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00539 (ACTG)

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA126361 OMIM: 135940.0002 dbSNP: rs558269137 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
FLG		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	-	-
CCDST	-	-	-	GRCh38	-	-

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Dermatitis, atopic, 2, susceptibility to	risk factor (1)	no assertion criteria provided	Oct 1, 2006	RCV000017715.5
Ichthyosis vulgaris	Pathogenic/Likely pathogenic (18)	criteria provided, multiple submitters, no conflicts	Jan 13, 2024	RCV000017714.61
Dermatitis, atopic, 2 Ichthyosis vulgaris	Pathogenic (2)	criteria provided, single submitter	Dec 4, 2017	RCV000191085.11
not provided	Pathogenic/Likely pathogenic (9)	criteria provided, multiple submitters, no conflicts	Jul 31, 2024	RCV000256057.42
Dermatitis, atopic, 2	Pathogenic (1)	criteria provided, single submitter	Oct 18, 2017	RCV000678372.4
Eczematoid dermatitis	Pathogenic (1)	criteria provided, single submitter	Aug 27, 2019	RCV001270060.3
FLG-related disorder	Pathogenic (3)	criteria provided, single submitter	-	RCV003398531.8
Autosomal dominant ichthyosis vulgaris	Pathogenic (1)	criteria provided, single submitter	Jul 2, 2020	RCV004786270.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Aug 27, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Eczematoid dermatitis Affected status: unknown Allele origin: germline	Knight Diagnostic Laboratories, Oregon Health and Sciences University Accession: SCV001448813.1 First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020	Number of individuals with the variant: 1 Clinical Features: Migraine (present) , Expressive language delay (present) , Receptive language delay (present) , Language impairment (present) , Autistic disorder of childhood onset (present) , Overgrowth … (more) Migraine (present) , Expressive language delay (present) , Receptive language delay (present) , Language impairment (present) , Autistic disorder of childhood onset (present) , Overgrowth (present) , Macrocephalus (present) , Obesity (present) , Upslanted palpebral fissure (present) , Narrow palpebral fissure (present) , Highly arched eyebrow (present) , Eczema (present) , Accelerated skeletal maturation (present) , Joint hypermobility (present) , Hypertensive disorder (present) (less) Sex: male
Pathogenic (Jan 01, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ichthyosis vulgaris Affected status: yes Allele origin: germline	Provincial Medical Genetics Program of British Columbia, University of British Columbia Accession: SCV002320786.1 First in ClinVar: Apr 08, 2022 Last updated: Apr 08, 2022	Sex: male
Pathogenic (Feb 17, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ichthyosis vulgaris Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV002512381.1 First in ClinVar: May 21, 2022 Last updated: May 21, 2022	Comment: ACMG classification criteria: PVS1, PM3 very strong Geographic origin: Brazil
Pathogenic (Jan 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ichthyosis vulgaris Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002580653.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PVS1, PS4_MOD, PM3, PP1	Number of individuals with the variant: 1 Sex: female
Pathogenic (Jan 13, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ichthyosis vulgaris Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV000328722.4 First in ClinVar: Oct 11, 2015 Last updated: Jun 09, 2024
Pathogenic (Aug 08, 2018)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000854988.1 First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=FLG Number of individuals with the variant: 3 Sex: mixed
Pathogenic (Aug 01, 2018)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Ichthyosis vulgaris Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000712217.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018	Publications: PubMed (6) PubMed: 16444271‚ 19538357‚ 19733298‚ 27363669‚ 27279822‚ 20573035 Comment: 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 … (more) 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. (less) Number of individuals with the variant: 1
Likely pathogenic (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Ichthyosis vulgaris Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001135412.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Pathogenic (Dec 04, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ichthyosis vulgaris Dermatitis, atopic, 2 Affected status: yes Allele origin: germline	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital Accession: SCV001423652.1 First in ClinVar: Jul 25, 2020 Last updated: Jul 25, 2020	Comment: [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 … (more) [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]. (less)
Pathogenic (Oct 01, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ichthyosis vulgaris Affected status: unknown Allele origin: germline	Johns Hopkins Genomics, Johns Hopkins University Accession: SCV001438366.1 First in ClinVar: Oct 25, 2020 Last updated: Oct 25, 2020	Publications: PubMed (3) PubMed: 16444271‚ 20739951‚ 21991953 Comment: 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 … (more) 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. (less)
Pathogenic (Jan 12, 2021)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Ichthyosis vulgaris Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV001478713.1 First in ClinVar: Feb 12, 2021 Last updated: Feb 12, 2021	Publications: PubMed (2) PubMed: 17417636‚ 31642606 Comment: 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 … (more) 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. (less)
Pathogenic (May 29, 2020)	criteria provided, single submitter (NYGC Assertion Criteria 2020) Method: clinical testing	Ichthyosis vulgaris Affected status: unknown Allele origin: germline	New York Genome Center Study: CSER-NYCKidSeq Accession: SCV002098025.1 First in ClinVar: Feb 20, 2022 Last updated: Feb 20, 2022	Clinical Features: Developmental regression (present) , Leukodystrophy (present) , Lower limb spasticity (present) , Absent speech (present) Secondary finding: no
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ichthyosis vulgaris Affected status: unknown Allele origin: unknown	Wangler Lab, Baylor College of Medicine Accession: SCV002577614.1 First in ClinVar: Oct 08, 2022 Last updated: Oct 08, 2022	Publications: PubMed (2) PubMed: 23947670‚ 27279822 Comment: This frameshift FLG variant at c.2282_2285del (p.S761Cfs36) was discovered on exome through the Texome Project (R01HG011795). This is a frameshift variant that is located in … (more) This frameshift FLG variant at c.2282_2285del (p.S761Cfs36) 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. (less) Age: 20-29 years Sex: male Ethnicity/Population group: male
Pathogenic (May 03, 2018)	criteria provided, single submitter (DGD Variant Analysis Guidelines) Method: clinical testing	Ichthyosis vulgaris Affected status: unknown Allele origin: germline	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia Accession: SCV000297112.4 First in ClinVar: Jul 31, 2016 Last updated: Dec 11, 2022
Pathogenic (Oct 18, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: provider interpretation, clinical testing	Dermatitis, atopic, 2 Affected status: yes Allele origin: maternal	Geisinger Autism and Developmental Medicine Institute, Geisinger Health System Accession: SCV000804438.2 First in ClinVar: Sep 07, 2018 Last updated: Dec 11, 2022	Publications: PubMed (1) PubMed: 16444271 Comment: 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 … (more) 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). (less) Observation 1: Clinical Features: Autistic disorder of childhood onset (present) , Intellectual disability (present) , Overgrowth (present) , Seizures (present) , Eczema (present) Age: 10-19 years Sex: male Secondary finding: no Testing laboratory: GeneDx Date variant was reported to submitter: 2017-09-28 Testing laboratory interpretation: Pathogenic Observation 2: Number of individuals with the variant: 1 Clinical Features: Autistic disorder of childhood onset (present) , Intellectual disability (present) , Overgrowth (present) , Seizures (present) , Eczema (present) Age: 10-19 years Sex: male Testing laboratory: GeneDx Date variant was reported to submitter: 2017-09-28 Testing laboratory interpretation: Pathogenic
Pathogenic (Aug 09, 2022)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Ichthyosis vulgaris (Autosomal recessive inheritance) Affected status: yes Allele origin: paternal	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV002764705.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Number of individuals with the variant: 1 Clinical Features: Atopic eczema (present) , Global developmental delay (present) , Elevated circulating hepatic transaminase concentration (present) , Hypopituitarism (present) , Ichthyosis (present)
Pathogenic (Oct 21, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ichthyosis vulgaris Affected status: yes Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV002061663.3 First in ClinVar: Jan 22, 2022 Last updated: Jan 21, 2023	Comment: PVS1, PS4, PM3
Pathogenic (Oct 29, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000321673.9 First in ClinVar: Oct 09, 2016 Last updated: Mar 04, 2023	Comment: 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 … (more) 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) (less)
Pathogenic (Feb 23, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ichthyosis vulgaris Affected status: yes Allele origin: unknown	3billion Accession: SCV003841493.1 First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023	Publications: PubMed (1) PubMed: 16444271 Comment: 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 … (more) 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. (less) Clinical Features: Abnormal facial shape (present) , Decreased circulating level of specific antibody (present) , Atopic eczema (present)
Pathogenic (May 19, 2023)	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020) Method: clinical testing	Ichthyosis vulgaris Affected status: unknown Allele origin: unknown	Illumina Laboratory Services, Illumina Accession: SCV004014698.1 First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023	Publications: PubMed (10) PubMed: 16815158‚ 31637781‚ 19874431‚ 23343419‚ 27363669‚ 16444271‚ 11121144‚ 27279822‚ 16550169‚ 16810297 Comment: 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 … (more) 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. (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	FLG-related disorders Affected status: yes Allele origin: germline	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV004046166.1 First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023	Comment: 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, … (more) 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. (less)
Pathogenic (Oct 02, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ichthyosis vulgaris Affected status: yes Allele origin: germline	Clinical Genomics Laboratory, Washington University in St. Louis Accession: SCV004177069.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023	Comment: 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 … (more) 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. (less)
Pathogenic (Jul 31, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV005090764.1 First in ClinVar: Aug 04, 2024 Last updated: Aug 04, 2024
Likely pathogenic (Jun 26, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Centre for Clinical Genetics and Genomic Diagnostics, Zealand University Hospital Accession: SCV005328430.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024
Pathogenic (Apr 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001245946.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: FLG: PVS1:Strong, PM2, PP1:Moderate, PS4:Moderate Number of individuals with the variant: 34
Pathogenic (Jun 20, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ichthyosis vulgaris (Autosomal unknown) Affected status: yes Allele origin: germline	Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center Accession: SCV005397312.1 First in ClinVar: Nov 17, 2024 Last updated: Nov 17, 2024	Publications: PubMed (2) PubMed: 16444271‚ 19501237 Comment: This sequence variant is a 4-nucleotide deletion (c.2282-2285delACTG) in the FLG gene that results in an early termition codon 36 amino acids downstream from the … (more) This sequence variant is a 4-nucleotide deletion (c.2282-2285delACTG) in the FLG gene that results in an early termition codon 36 amino acids downstream from the frameshift at residue 761. The early termition results in a non-functiol allele through loss of FLG expression (PMID: 16444271). This is a previously reported, well known variant (ClinVar) that is also referred to as 2282del4 in the literature. This variant is common in control population datasets (gnomAD database 3716/282796 alleles, or 1.3%), found mostly in individuals of European descent. Multiple studies, including a large meta-alysis, find that this variant is significantly associated with atopic dermatitis (PMID: 19501237). Given the evidence, we consider this variant to be pathogenic. ACMG Criteria: PS4, PVS1 (less)
Pathogenic (Jul 02, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal dominant ichthyosis vulgaris Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005398584.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (5) PubMed: 16444271‚ 17291859‚ 29444371‚ 30681730‚ 31642606 Comment: Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease … (more) Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0108 - This gene is known to be associated with both recessive and dominant disease. Heterozygotes may be asymptomatic or have a mild phenotype, whereas homozygotes and compound heterozygotes are more severely affected (OMIM). (N) 0112 - Variants in this gene are known to have reduced penetrance (PMID: 17291859, PMID: 30681730). (N) 0204 - Variant is predicted to result in a truncated protein with more than 1/3 of the protein affected (exon 3 of 3). (P) 0251 - Variant is heterozygous. (N) 0303 - Variant is present in gnomAD >=0.01 (3638 heterozygotes, 39 homozygotes). (B) 0600 - Variant is located upstream of multiple filaggrin domains (NCBI, PDB). (N) 0701 - Comparable truncating variants have very strong previous evidence for pathogenicity. Many pathogenic truncating variants downstream (ClinVar). (P) 0801 - The variant has strong previous evidence of pathogenicity in unrelated individuals with autosomal dominant and recessive ichthyosis vulgaris and atopic dermatitis (ClinVar, PMID: 16444271, PMID: 29444371, PMID: 31642606). (P) 0902 - Moderate evidence for segregation with disease. The variant has been shown to segregate with disease in multiple families, however majority are compound heterozygous with p.(Arg501*) variant (PMID: 16444271). (P) 1001 - Strong functional evidence supporting abnormal protein function. A complete loss of filaggrin peptide production was observed by immunohistochemistry in a skin biopsy from a patient (PMID: 16444271). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign (less)
Pathogenic (Oct 01, 2006)	no assertion criteria provided Method: literature only	ICHTHYOSIS VULGARIS Affected status: not provided Allele origin: germline	OMIM Accession: SCV000037991.2 First in ClinVar: Apr 04, 2013 Last updated: Aug 13, 2015	Publications: PubMed (4) PubMed: 16444271‚ 16550169‚ 16815158‚ 17030239 Comment on evidence: For discussion of the 4-bp deletion in the FLG gene (2282del4) that was found in compound heterozygous state in patients with ichthyosis vulgaris (146700) by … (more) For discussion of the 4-bp deletion in the FLG gene (2282del4) that was found in compound heterozygous state in patients with ichthyosis vulgaris (146700) by Smith et al. (2006), see 135940.0001. For discussion of the 2282del4 deletion in the FLG gene that was found in compound heterozygous state in patients with atopic dermatitis (605803) by Palmer et al. (2006), see 135940.0001. Weidinger et al. (2006) found a significant association between atopic dermatitis, in particular the extrinsic type, and the R501X and 2282del4 mutations; Marenholz et al. (2006) replicated the association and also found that the presence of 2 null alleles was an independent risk factor for asthma in children with eczema. See 135940.0001. (less)
risk factor (Oct 01, 2006)	no assertion criteria provided Method: literature only	DERMATITIS, ATOPIC, 2, SUSCEPTIBILITY TO Affected status: not provided Allele origin: germline	OMIM Accession: SCV000037992.2 First in ClinVar: Apr 04, 2013 Last updated: Aug 13, 2015	Publications: PubMed (4) PubMed: 16444271‚ 16550169‚ 16815158‚ 17030239 Comment on evidence: For discussion of the 4-bp deletion in the FLG gene (2282del4) that was found in compound heterozygous state in patients with ichthyosis vulgaris (146700) by … (more) For discussion of the 4-bp deletion in the FLG gene (2282del4) that was found in compound heterozygous state in patients with ichthyosis vulgaris (146700) by Smith et al. (2006), see 135940.0001. For discussion of the 2282del4 deletion in the FLG gene that was found in compound heterozygous state in patients with atopic dermatitis (605803) by Palmer et al. (2006), see 135940.0001. Weidinger et al. (2006) found a significant association between atopic dermatitis, in particular the extrinsic type, and the R501X and 2282del4 mutations; Marenholz et al. (2006) replicated the association and also found that the presence of 2 null alleles was an independent risk factor for asthma in children with eczema. See 135940.0001. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001973529.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Likely pathogenic (Sep 17, 2024)	no assertion criteria provided Method: clinical testing	FLG-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004104648.3 First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024	Comment: The FLG c.2282_2285delCAGT variant is predicted to result in a frameshift and premature protein termination (p.Ser761Cysfs36). This variant has been reported in the heterozygous, compound … (more) The FLG c.2282_2285delCAGT variant is predicted to result in a frameshift and premature protein termination (p.Ser761Cysfs36). 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. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: unknown	Department of Pathology and Laboratory Medicine, Sinai Health System Additional submitter: Franklin by Genoox Study: The Canadian Open Genetics Repository (COGR) Accession: SCV001552929.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021	Comment: The FLGÂ¬â€ p.S761Cfs36 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; … (more) The FLGÂ¬â€ p.S761Cfs36 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).Â¬â€ 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 laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV001806900.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001743042.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
not provided (-)	no classification provided Method: phenotyping only	FLG-Related Disorder Affected status: yes, unknown Allele origin: maternal, paternal, unknown	GenomeConnect, ClinGen Accession: SCV000840291.2 First in ClinVar: Oct 14, 2018 Last updated: Feb 11, 2022	Comment: 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 … (more) 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. (less) Observation 1: Number of individuals with the variant: 1 Clinical Features: Decreased fetal movement (present) , Abnormal delivery (present) , Pregnancy history (present) , Short stature (present) , Failure to thrive (present) , Abnormality of the … (more) Decreased fetal movement (present) , Abnormal delivery (present) , Pregnancy history (present) , Short stature (present) , Failure to thrive (present) , Abnormality of the chin (present) , Abnormal facial shape (present) , Abnormal hair morphology (present) , Abnormal oral cavity morphology (present) , Abnormality of the mouth (present) , Abnormality of the neck (present) , Abnormality of the nose (present) , Abnormal skull morphology (present) , Myopia (present) , Ear malformation (present) , Cognitive impairment (present) , Abnormality of coordination (present) , Hypertonia (present) , Memory impairment (present) , Autistic behavior (present) , Abnormal aggressive, impulsive or violent behavior (present) , Anxiety (present) , Compulsive behaviors (present) , Short attention span (present) , Cafe au lait spots, multiple (present) , Hypopigmentation of the skin (present) , Hyperhidrosis (present) , Cardiac arrhythmia (present) , Abnormal EKG (present) , Abnormal cardiovascular system morphology (present) , Feeding difficulties (present) , Abnormal stomach morphology (present) , Abnormal intestine morphology (present) , Immunodeficiency (present) , Recurrent infections (present) , Gingivitis (present) , Abnormal dental morphology (present) , Abnormality of primary teeth (present) (less) Indication for testing: Diagnostic Age: 10-19 years Sex: female Testing laboratory: GeneDx Date variant was reported to submitter: 2020-10-16 Testing laboratory interpretation: Pathogenic Observation 2: Number of individuals with the variant: 1 Clinical Features: Failure to thrive (present) , Short attention span (present) , Asthma (present) , Feeding difficulties (present) , Abnormal esophagus morphology (present) Indication for testing: Diagnostic Age: 0-9 years Sex: male Method: Sanger Sequencing Testing laboratory: GeneDx Date variant was reported to submitter: 2021-08-31 Testing laboratory interpretation: Pathogenic Observation 3: Number of individuals with the variant: 1 Clinical Features: Abnormality of eye movement (present) , Myopia (present) , Abnormality of the nervous system (present) , Cognitive impairment (present) , Abnormality of coordination (present) , … (more) Abnormality of eye movement (present) , Myopia (present) , Abnormality of the nervous system (present) , Cognitive impairment (present) , Abnormality of coordination (present) , EEG abnormality (present) , Seizure (present) , Abnormal esophagus morphology (present) , Abnormal stomach morphology (present) , Abnormal large intestine morphology (present) , Abnormal erythrocyte morphology (present) (less) Indication for testing: Diagnostic Age: 10-19 years Sex: female Testing laboratory: Baylor Genetics Date variant was reported to submitter: 2014-07-28 Testing laboratory interpretation: Pathogenic Observation 4: Number of individuals with the variant: 1 Clinical Features: Abnormality of the chin (present) , Orofacial cleft (present) , Abnormal facial shape (present) , Abnormal hair morphology (present) , Abnormal oral cavity morphology (present) … (more) Abnormality of the chin (present) , Orofacial cleft (present) , Abnormal facial shape (present) , Abnormal hair morphology (present) , Abnormal oral cavity morphology (present) , Abnormality of the mouth (present) , Abnormality of the neck (present) , Abnormality of the nose (present) , Abnormal skull morphology (present) , Oral-pharyngeal dysphagia (present) , Abnormality of eye movement (present) , Abnormality of globe size (present) , Abnormality iris morphology (present) , Abnormal lens morphology (present) , Abnormality of vision (present) , Myopia (present) , Hypermetropia (present) , Abnormal optic nerve morphology (present) , Abnormal retinal morphology (present) , Ptosis (present) , Ear malformation (present) , Conductive hearing impairment (present) , Sensorineural hearing loss disorder (present) , Mixed hearing impairment (present) , Hearing impairment (present) , Tinnitus (present) , Hyperacusis (present) , Vertigo (present) , Abnormality of the nervous system (present) , Cerebral palsy (present) , Cognitive impairment (present) , Abnormality of coordination (present) , EEG abnormality (present) , Encephalopathy (present) , Hypertonia (present) , Generalized hypotonia (present) , Memory impairment (present) , Movement disorder (present) , Parkinsonian disorder (present) , Seizure (present) , Autistic behavior (present) , Bipolar affective disorder (present) , Schizophrenia (present) , Motor stereotypies (present) , Abnormal aggressive, impulsive or violent behavior (present) , Anxiety (present) , Depression (present) , Delusion (present) , Hallucinations (present) , Compulsive behaviors (present) , Psychotic disorder (present) , Short attention span (present) , Atrophic scars (present) , Cafe au lait spots, multiple (present) , Hyperpigmentation of the skin (present) , Hypopigmentation of the skin (present) , Hypohidrosis (present) , Hyperhidrosis (present) , Fragile skin (present) , Thickened skin (present) , Hyperextensible skin (present) , Cutis laxa (present) , Vascular dilatation (present) , Cardiac arrhythmia (present) , Abnormal EKG (present) , Arterial dissection (present) , Cardiomyopathy (present) , Abnormality of the cardiovascular system (present) , Abnormal cardiovascular system morphology (present) , Hypertensive disorder (present) , Hypercholesterolemia (present) , Stroke disorder (present) (less) Indication for testing: Diagnostic Age: 20-29 years Sex: female Method: Sanger Sequencing Testing laboratory: GeneDx Date variant was reported to submitter: 2017-09-21 Testing laboratory interpretation: Pathogenic
Uncertain significance (Jul 08, 2015)	Flagged submission flagged submission (Yang et al. 2013) Method: clinical testing Reason: Older claim that does not account for recent evidence Source: ClinGen	Ichthyosis vulgaris Dermatitis, atopic, 2 (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Baylor Genetics Study: Adult_WES Accession: SCV000245481.1 First in ClinVar: Sep 29, 2015 Last updated: Sep 29, 2015	Publications: PubMed (16) PubMed: 26633545‚ 16444271‚ 21777221‚ 23039796‚ 23343419‚ 23947670‚ 18325573‚ 19501237‚ 19733298‚ 21377035‚ 21564328‚ 19538357‚ 20573035‚ 21365004‚ 22403702‚ 23166590 Comment: 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 … (more) 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. (less) Number of individuals with the variant: 161 Family history: yes Sex: mixed
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Comment:

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.

Comment:

[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].

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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).

Comment:

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)

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

This sequence variant is a 4-nucleotide deletion (c.2282-2285delACTG) in the FLG gene that results in an early termition codon 36 amino acids downstream from the frameshift at residue 761. The early termition results in a non-functiol allele through loss of FLG expression (PMID: 16444271). This is a previously reported, well known variant (ClinVar) that is also referred to as 2282del4 in the literature. This variant is common in control population datasets (gnomAD database 3716/282796 alleles, or 1.3%), found mostly in individuals of European descent. Multiple studies, including a large meta-alysis, find that this variant is significantly associated with atopic dermatitis (PMID: 19501237). Given the evidence, we consider this variant to be pathogenic. ACMG Criteria: PS4, PVS1

Comment:

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0108 - This gene is known to be associated with both recessive and dominant disease. Heterozygotes may be asymptomatic or have a mild phenotype, whereas homozygotes and compound heterozygotes are more severely affected (OMIM). (N) 0112 - Variants in this gene are known to have reduced penetrance (PMID: 17291859, PMID: 30681730). (N) 0204 - Variant is predicted to result in a truncated protein with more than 1/3 of the protein affected (exon 3 of 3). (P) 0251 - Variant is heterozygous. (N) 0303 - Variant is present in gnomAD >=0.01 (3638 heterozygotes, 39 homozygotes). (B) 0600 - Variant is located upstream of multiple filaggrin domains (NCBI, PDB). (N) 0701 - Comparable truncating variants have very strong previous evidence for pathogenicity. Many pathogenic truncating variants downstream (ClinVar). (P) 0801 - The variant has strong previous evidence of pathogenicity in unrelated individuals with autosomal dominant and recessive ichthyosis vulgaris and atopic dermatitis (ClinVar, PMID: 16444271, PMID: 29444371, PMID: 31642606). (P) 0902 - Moderate evidence for segregation with disease. The variant has been shown to segregate with disease in multiple families, however majority are compound heterozygous with p.(Arg501*) variant (PMID: 16444271). (P) 1001 - Strong functional evidence supporting abnormal protein function. A complete loss of filaggrin peptide production was observed by immunohistochemistry in a skin biopsy from a patient (PMID: 16444271). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign

Comment:

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.

Comment:

The FLGÂ¬â€ 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).Â¬â€ 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 laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic.

Comment:

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.

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Spectrum of ichthyoses in an Austrian ichthyosis cohort from 2004 to 2017.	Seidl-Philipp M	Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG	2020	PMID: 31642606
Prevalence of FLG loss-of-function mutations R501X, 2282del4, and R2447X in Spanish children with atopic dermatitis.	González-Tarancón R	Pediatric dermatology	2020	PMID: 31637781
Filaggrin gene mutations in hand eczema patients in the Indian subcontinent: A prospective case-control study.	Handa S	Contact dermatitis	2019	PMID: 30681730
Whole-exome sequencing for diagnosis of hereditary ichthyosis.	Sitek JC	Journal of the European Academy of Dermatology and Venereology : JEADV	2018	PMID: 29444371
The study of filaggrin gene mutations and copy number variation in atopic dermatitis patients from Volga-Ural region of Russia.	Gimalova GF	Gene	2016	PMID: 27363669
The prevalence of mutations in the gene encoding filaggrin in the population of Polish patients with atopic dermatitis.	Woźniak M	Postepy dermatologii i alergologii	2016	PMID: 27279822
Molecular diagnostic experience of whole-exome sequencing in adult patients.	Posey JE	Genetics in medicine : official journal of the American College of Medical Genetics	2016	PMID: 26633545
Filaggrin compound heterozygous patients carry mutations in trans position.	Carlsen BC	Experimental dermatology	2013	PMID: 23947670
Filaggrin mutations are strongly associated with contact sensitization in individuals with dermatitis.	Thyssen JP	Contact dermatitis	2013	PMID: 23343419
Impact of atopic dermatitis and loss-of-function mutations in the filaggrin gene on the development of occupational irritant contact dermatitis.	Visser MJ	The British journal of dermatology	2013	PMID: 23039796
Clinical presentation of atopic dermatitis by filaggrin gene mutation status during the first 7 years of life in a prospective cohort study.	Carson CG	PloS one	2012	PMID: 23166590
Interplay of filaggrin loss-of-function variants, allergic sensitization, and eczema in a longitudinal study covering infancy to 18 years of age.	Ziyab AH	PloS one	2012	PMID: 22403702
Filaggrin loss-of-function mutation R501X and 2282del4 carrier status is associated with fissured skin on the hands: results from a cross-sectional population study.	Thyssen JP	The British journal of dermatology	2012	PMID: 21777221
The filaggrin null genotypes R501X and 2282del4 seem not to be associated with psoriasis: results from general population study and meta-analysis.	Thyssen JP	Journal of the European Academy of Dermatology and Venereology : JEADV	2012	PMID: 21564328
Filaggrin mutations associated with skin and allergic diseases.	Irvine AD	The New England journal of medicine	2011	PMID: 21991953
Loss-of-function variants in the filaggrin gene are a significant risk factor for peanut allergy.	Brown SJ	The Journal of allergy and clinical immunology	2011	PMID: 21377035
Filaggrin gene defects are independent risk factors for atopic asthma in a Polish population: a study in ECAP cohort.	Ponińska J	PloS one	2011	PMID: 21365004
Eczema prevalence in the United States: data from the 2003 National Survey of Children's Health.	Shaw TE	The Journal of investigative dermatology	2011	PMID: 20739951
Filaggrin gene variants and atopic diseases in early childhood assessed longitudinally from birth.	Bønnelykke K	Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology	2010	PMID: 20573035
Analysis of four prevalent filaggrin mutations (R501X, 2282del4, R2447X and S3247X) in Austrian and German patients with atopic dermatitis.	Greisenegger E	Journal of the European Academy of Dermatology and Venereology : JEADV	2010	PMID: 19874431
Filaggrin mutations in the onset of eczema, sensitization, asthma, hay fever and the interaction with cat exposure.	Schuttelaar ML	Allergy	2009	PMID: 19839980
Filaggrin mutations that confer risk of atopic dermatitis confer greater risk for eczema herpeticum.	Gao PS	The Journal of allergy and clinical immunology	2009	PMID: 19733298
Association of Filaggrin loss-of-function-mutations with atopic dermatitis and asthma in the Early Treatment of the Atopic Child (ETAC) population.	Müller S	Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology	2009	PMID: 19538357
Meta-analysis of filaggrin polymorphisms in eczema and asthma: robust risk factors in atopic disease.	Rodríguez E	The Journal of allergy and clinical immunology	2009	PMID: 19501237
The burden of disease associated with filaggrin mutations: a population-based, longitudinal birth cohort study.	Henderson J	The Journal of allergy and clinical immunology	2008	PMID: 18325573
Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema.	Sandilands A	Nature genetics	2007	PMID: 17417636
Unique mutations in the filaggrin gene in Japanese patients with ichthyosis vulgaris and atopic dermatitis.	Nomura T	The Journal of allergy and clinical immunology	2007	PMID: 17291859
Filaggrin loss-of-function mutations predispose to phenotypes involved in the atopic march.	Marenholz I	The Journal of allergy and clinical immunology	2006	PMID: 17030239
Loss-of-function variations within the filaggrin gene predispose for atopic dermatitis with allergic sensitizations.	Weidinger S	The Journal of allergy and clinical immunology	2006	PMID: 16815158
Prevalent and rare mutations in the gene encoding filaggrin cause ichthyosis vulgaris and predispose individuals to atopic dermatitis.	Sandilands A	The Journal of investigative dermatology	2006	PMID: 16810297
Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis.	Palmer CN	Nature genetics	2006	PMID: 16550169
Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris.	Smith FJ	Nature genetics	2006	PMID: 16444271
Loss of normal profilaggrin and filaggrin in flaky tail (ft/ft) mice: an animal model for the filaggrin-deficient skin disease ichthyosis vulgaris.	Presland RB	The Journal of investigative dermatology	2000	PMID: 11121144
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=FLG	-	-	-	-
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Text-mined citations for rs558269137 ...

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Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs558269137 ...