rs558269137
Variant summary
Our verdict is Likely pathogenic. The variant received 7 ACMG points: 9P and 2B. PVS1PP5BS1_SupportingBS2_Supporting
The NM_002016.2(FLG):c.2282_2285delCAGT(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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_002016.2 frameshift
Scores
Clinical Significance
Conservation
Publications
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ACMG classification
Our verdict: Likely_pathogenic. The variant received 7 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| FLG | NM_002016.2 | c.2282_2285delCAGT | p.Ser761CysfsTer36 | frameshift_variant | Exon 3 of 3 | ENST00000368799.2 | NP_002007.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| FLG | ENST00000368799.2 | c.2282_2285delCAGT | p.Ser761CysfsTer36 | frameshift_variant | Exon 3 of 3 | 1 | NM_002016.2 | ENSP00000357789.1 |
Frequencies
GnomAD3 genomes 0.0126 AC: 1913AN: 151856Hom.: 18 Cov.: 29 show subpopulations
GnomAD2 exomes AF: 0.0129 AC: 3237AN: 251484 AF XY: 0.0128 show subpopulations
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0196 AC: 28705AN: 1461820Hom.: 396 AF XY: 0.0191 AC XY: 13885AN XY: 727210 show subpopulations
Age Distribution
GnomAD4 genome 0.0126 AC: 1913AN: 151974Hom.: 18 Cov.: 29 AF XY: 0.0116 AC XY: 865AN XY: 74280 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Ichthyosis vulgaris Pathogenic:21
The c.2282_2285del variant in the FLG gene is a loss of function variant not predicted to undergo nonsense mediated decay as it is in the last exon but it alters >10% of the protein for a gene where loss of function variants have been described as a causing mechanism for the gene (PVS1_strong). The variant has been described in multiple independent pacients with Ichthyosis vulgaris and it has been significantly associated with atopic dermatitis in a case-control study (OR=8.94, P=7.8 x 10^-7) (PMID: PMID: 30681730)(PS4_strong). With all the available evidence, the variant is classified as likely pathogenic. -
PVS1, PS4, PM3 -
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 -
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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. -
ACMG Criteria: PVS1, PS4, PM3, PP1, PP5; Variant was found in homozygous state. -
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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. -
PVS1, PS4, PM3 -
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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. -
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. -
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. -
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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. -
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ACMG classification criteria: PVS1, PM3 very strong -
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. -
not provided Pathogenic:10
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FLG: PM3:Very Strong, PP1:Strong, PVS1:Strong, PM2:Supporting -
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) -
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. -
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Ichthyosis vulgaris;C1853965:Dermatitis, atopic, 2 Pathogenic:3Uncertain:1
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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. -
[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]. -
FLG-related disorder Pathogenic:2Other:1
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. -
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. -
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. -
Inborn genetic diseases Pathogenic:1
The c.2282_2285delCAGT (p.S761Cfs*36) alteration, located in exon 3 (coding exon 2) of the FLG gene, consists of a deletion of 4 nucleotides from position 2282 to 2285, causing a translational frameshift with a predicted alternate stop codon after 36 amino acids. This variant is not expected to trigger nonsense-mediated mRNA decay and impacts the last 81% of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). Based on data from gnomAD, the alternate allele has an overall frequency of 1.314% (3716/282796) total alleles studied. The highest observed frequency was 2.161% (2791/129164) of European (non-Finnish) alleles. This variant has been identified in the homozygous state and/or in conjunction with other variant(s) in this same gene in individual(s) with features consistent with ichthyosis vulgaris and segregated with disease in at least one family (Sandilands, 2007; Van Leersum, 2020; Palmer, 2006). Based on the available evidence, this alteration is classified as pathogenic. -
Eczematoid dermatitis Pathogenic:1
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Autosomal dominant ichthyosis vulgaris Pathogenic:1
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 -
Autosomal recessive congenital ichthyosis Pathogenic:1
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Dermatitis, atopic, 2 Pathogenic:1
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
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at