rs61816761
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 16P and 1B. PVS1PP5_Very_StrongBS1_Supporting
The NM_002016.2(FLG):c.1501C>T(p.Arg501*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.017 in 1,613,302 control chromosomes in the GnomAD database, including 315 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_002016.2 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.0104 AC: 1580AN: 151398Hom.: 17 Cov.: 30
GnomAD3 exomes AF: 0.00937 AC: 2354AN: 251350Hom.: 18 AF XY: 0.00935 AC XY: 1270AN XY: 135840
GnomAD4 exome AF: 0.0176 AC: 25781AN: 1461786Hom.: 298 Cov.: 102 AF XY: 0.0171 AC XY: 12440AN XY: 727198
GnomAD4 genome 0.0104 AC: 1580AN: 151516Hom.: 17 Cov.: 30 AF XY: 0.00919 AC XY: 680AN XY: 73994
ClinVar
Submissions by phenotype
Ichthyosis vulgaris Pathogenic:18Other:1
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The FLG c.1501C>T (p.Arg501Ter) variant has been reported in over 150 individuals affected with ichthyosis vulgaris and atopic dermatitis and is reported to segregate with disease in multiple families (Palmer CN et al., PMID; 16550169; Smith FJ et al., PMID: 16444271). Of those individuals, the variant has been identified in a homozygous state in at least nine individuals, in a compound heterozygous state with a pathogenic or likely pathogenic variant in at least 50 individuals, and in a heterozygous state in over 100 individuals (Gimalova GF et al., PMID: 27363669; Marenholz I et al., PMID: 17030239; Palmer CN et al., PMID; 16550169; Polcari I et al., PMID; 24920311; Smith FJ et al., PMID: 16444271; Weidinger S et al., PMID: 16815158; Wozniak M et al., PMID: 27279822). The highest population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 1.64% in the European (non-Finnish) population which is consistent with the reported incidence of low penetrance ichthyosis vulgaris in heterozygotes. This variant has been reported in the ClinVar database as a pathogenic variant by 23 submitters and likely pathogenic by one submitter. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. -
Variant interpreted as Pathogenic and reported on 08-31-2021 by Lab or GTR ID 26957. 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. -
Based on the classification scheme VCGS_Germline_v1.3.2, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with ichthyosis vulgaris. (I) 0108 - This gene is associated with both recessive and dominant disease. Biallelic truncating variants tend to result in a more severe condition (PMIDs: 17291859, 30681730). (I) 0112 - The condition associated with this gene has incomplete penetrance. Heterozygous carriers are more likely to be asymptomatic than individuals with biallelic variants (PMIDs: 17291859, 30681730). (I) 0204 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with at least 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0310 - Variant is present in gnomAD (v2) >=0.001 and <0.01 for a dominant condition (2611 heterozygotes, 21 homozygotes). (I) 0600 - Variant is located upstream of multiple filaggrin domains (DECIPHER). (I) 0701 - Other truncating variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many other truncating variants have previously been reported as pathogenic in patients with ichthyosis vulgaris (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported as pathogenic in multiple patients and their families with both dominant and recessive ichthyosis vulgaris, and is considered to be one of the most common pathogenic variants in the European population (ClinVar, HGMD, PMIDs: 16444271, 32066784, 32325630). (SP) 1207 - Parental origin of the variant is unresolved. Trio analysis has shown that this variant is heterozygous in this individual's mother and father, as it is also heterozygous in this individual it is not clear which parent it was inherited from. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Criteria applied: PVS1,PM3_VSTR -
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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. However, 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%. And it has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000016319 / PMID: 16444271 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
PVS1, PS4, PM3 -
This sequence variant is a single nucleotide substitution (C>T) at coding nucleotide position 1501 in the FLG gene which results in the generation of a premature stop codon at residue 501 of the FLG protein. This variant is predicted to generate a non-functional allele through truncation of important functional domains. This is a well-known pathogenic variant (ClinVar 16319) that has been observed in many individuals in the literature with atopic dermatitis, ichthyosis vulgaris, and eczema (PMID: 19839980, 22164253, 24920311, 31365035). This variant is one of the most common pathogenic alleles in the FLG gene and is observed in control population datasets (gnomAD database 3934/402748 alleles or 0.9768%). Functional evidence confirms individuals carrying homozygous alleles for this variant display complete loss of FLG expression. Additionally, homozygous or compound heterozygous carriers for truncating FLG variants have more severe disease (PMID: 16444271). Given the evidence, we consider this variant to be pathogenic. ACMG Criteria: PS3, PS4, PVS1 -
The p.Arg501X variant in FLG is a well-established pathogenic variant associated with ichthyosis vulgaris (Smith 2006, Rodriguez 2009, Gruber 2011). This varian t has been identified in 0.9% (2595/276976) of total chromosomes, including 19 h omozygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinsti tute.org; dbSNP rs61816761), which is consistent with the reported incidence of ichthyosis vulgaris and the incomplete penetrance in heterozygotes. This nonsens e variant leads to a premature termination codon at position 501, resulting in a n absence of protein as demonstrated by studies in homozygotes and compound hete rozygotes that carried another nonsense variant (Smith 2006, Gruber 2011). Haplo insufficiency of FLG is an established disease mechanism for ichthyosis vulgaris , while biallelic loss of function is associated with a severe phenotype similar to classic lamellar ichthyosis (Smith 2006). In addition, the p.Arg501X and oth er loss-of-function variants in FLG have been associated with increased risk for eczema (OR 2.5-3.7; Henderson 2008, Rodriguez 2009, Schuttelaar 2009, Ziyab 201 2). In summary, the p.Arg501X variant meets criteria to be classified as pathoge nic for ichthyosis vulgaris in an autosomal dominant manner with reduced penetra nce. ACMG/AMP criteria applied: PVS1; PS4; PP1_Strong. -
This patient is a carrier of a heterozygous pathogenic variant in the FLG gene implicated in causing ichthyosis vulgaris (MIM 146700), as well as being a risk factor for atopic dermatitis (MIM 605803). The FLG variant (c.1501C>T) is a nonsense mutation that is predicted to prematurely truncate the transcript. It has been identified in many patients in the literature and is one of the most common pathogenic mutations identified in this gene in populations of European ancestry (Smith et al. 2006, PMID: 16444271; Weidinger et al. 2007, PMID: 16815158; Palmer et al. 2008, PMID: 16550169). Carriers of this variant have reported to be either asymptomatic with no discernible presentation or be affected by a mild form of icthythosis (Smith et al. 2006, PMID: 16444271) and are at an increased risk for having atopic disease (Palmer et al. 2008, PMID: 16550169). -
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NM_002016.1:c.1501C>T in the FLG gene has an allele frequency of 0.016 in European (no Finnish) subpopulation in the gnomAD database.This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. It was detected in multiple individuals, compound heterozygous with c.2282del4 (PMID:16444271). The patient's phenotype is highly specific for FLG (PMID:16444271). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PVS1; PM3; PP4. -
The FLG c.1501C>T p.(Arg501Ter) nonsense variant occurs in the last exon of the gene and may escape nonsense-mediated mRNA decay. The p.Arg501Ter variant is the most common disease-causing variant observed in individuals with ichthyosis vulgaris (PMID 16444271; 16550169; 17030239; 16815158; 24920311; 27279822; 27363669; 31637781). Inheritance can be autosomal dominant or recessive, with autosomal recessive inheritance showing a more severe phenotype. The p.Arg501Ter variant has been shown to segregate with disease across multiple families (PMID 16444271; 16550169). The highest frequency of this allele in the Genome Aggregation Database is 0.01732 in the European (non-Finnish) population (version 3.1.2). This allele frequency among presumed unaffected individuals is high, but is consistent with the estimates of disease prevalence and penetrance. Functional studies conducted in patient cells demonstrated that this variant impacts protein function (PMID: 16444271). Based on the available evidence, the c.1501C>T p.(Arg501Ter) variant is classified as pathogenic for ichthyosis vulgaris. -
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not provided Pathogenic:10
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FLG: PP1:Strong, PVS1:Strong, PS4:Moderate, PM2:Supporting -
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Reported as one of the most common pathogenic FLG variants observed in Caucasian individuals of North/West-European descent with ichthyosis vulgaris (Smith et al., 2006); Loss-of-function FLG variants are associated with increased risk for atopic dermatitis and asthma (Henderson et al., 2008; Komova et al., 2014; Muller et al., 2009; Gao et al., 2009); Nonsense 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 homozygous for this variant (Smith et al., 2006); This variant is associated with the following publications: (PMID: 29431110, 18412804, 24920311, 19839980, 20426775, 21777221, 23039796, 23343419, 23947670, 19501237, 21377035, 23993222, 21564328, 17657246, 25333069, 23352160, 20573035, 21365004, 22403702, 23166590, 19538357, 19733298, 25390410, 16444271, 27462351, 27363669, 24251354, 26451970, 27279822, 18325573, 29444371, 29791750, 29428354, 28213896, 29068602, 28730607, 29054605, 28164424, 31427378, 31365035, 30739909, 25747786, 32603359, 32371413, 33326653, 17164798, 33144682, 33258288) -
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The FLG p.R501* variant is a common pathogenic variant associated with ichthyosis vulgaris; individuals compound heterozygous or homozygous for the p.R501* variant were found to have a more severe phenotype while heterozygotes had a mild phenotype (Smith_2006_PMID:16444271; Palmer_2006_PMID:16550169). Unaffected individuals with the p.R501* variant have also been identified, suggesting incomplete penetrance. The p.R501* variant was found to strongly predispose for atopic dermatitis and asthma (Palmer_2006_PMID:16550169; Henderson_2008_PMID:18325573). The variant was identified in dbSNP (ID: rs61816761), ClinVar (classified as pathogenic by six submitters) and LOVD 3.0 (classified as pathogenic). The variant was identified in control databases in 2653 of 282652 chromosomes (21 homozygous) at a frequency of 0.009386 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 2114 of 129034 chromosomes (freq: 0.01638), Ashkenazi Jewish in 128 of 10366 chromosomes (freq: 0.01235), Other in 69 of 7214 chromosomes (freq: 0.009565), African in 106 of 24920 chromosomes (freq: 0.004254), Latino in 145 of 35438 chromosomes (freq: 0.004092), European (Finnish) in 51 of 25120 chromosomes (freq: 0.00203), South Asian in 39 of 30616 chromosomes (freq: 0.001274), and East Asian in 1 of 19944 chromosomes (freq: 0.00005). The c.1501C>T variant leads to a premature stop codon at position 501 which is predicted to lead to 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 are known to cause the disorder. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -
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FLG-related disorder Pathogenic:3
The FLG c.1501C>T variant is predicted to result in premature protein termination (p.Arg501*). This variant is the most common pathogenic variant in this gene and is more commonly observed in individuals of European ancestry (Garrett et al. 2013. PubMed ID: 23993222). Individuals who are heterozygous for this variant have been reported to be asymptomatic (reduced penetrance) or affected by a milder form of ichthyosis, and are at an increased risk for atopic dermatitis. Individuals who are homozygous for this variant have a more severe phenotype, such as pronounced ichthyosis vulgaris, greater risk of early and severe atopic dermatitis, rhinitis, possible food allergies, asthma, hand eczema, elevated total and specific immunoglobulin E, palmar hyperlinearity and keratosis pilaris (Smith et al. 2006. PubMed ID: 16444271; Carlsen et al. 2013. PubMed ID: 23947670; Henderson et al. 2008. PubMed ID: 18325573; van Ginkel et al. 2015. PubMed ID: 25620092; Ogrodowczyk et al. 2014. PubMed ID: 25276250). This variant is reported in 1.6% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in FLG are expected to be pathogenic. This variant is interpreted as pathogenic. -
The FLG c.1501C>T (p.Arg501Ter) variant is a stop-gained variant that is predicted to result in a premature termination or absence of the protein. In one study, the p.Arg501Ter variant is reported to be the most common disease-causing variant in individuals with atopic dermatitis (González-Tarancón et al. 2020). Across a selection of available literature, the variant has been identified in a homozygous state in at least nine individuals, in a compound heterozygote state in at least 54 individuals, and in a heterozygous state in over 100 individuals, all affected with atopic dermatitis or ichthyosis vulgaris (Marenholz et al. 2006; Palmer et al. 2006; Smith et al. 2006; Weidinger et al. 2006; Polcari et al. 2014; Gimalova et al. 2016; Woźniak et al. 2016). All affected homozygotes or compound heterozygotes showed more severe presentations of ichthyosis vulgaris than individuals determined to be heterozygous for this variant. The p.Arg501Ter variant segregates in an autosomal recessive pattern across three generations in at least one family with ichthyosis vulgaris, and segregates in an autosomal dominant pattern with variable presentations of ichthyosis vulgaris and atopic dermatitis with expected reduced penetrance across three generations in at least two families (Palmer et al. 2006; Smith et al. 2006). The p.Arg501Ter variant was identified in ten of 732 control subjects in a heterozygous state (Marenholz et al. 2006; Polcari et al. 2014; Gimalova et al. 2016), and is reported at a frequency of 0.01638 in the European (non-Finnish) population of the Genome Aggregation Database. This allele frequency among presumed unaffected individuals is high, but is consistent with the disease prevalence and penetrance estimates. Odds ratios of 4.1 to 6.7 are described when comparing the frequency of this variant among affected vs. unaffected individuals (Marenholz et al. 2006; Weidinger et al. 2006). Smith et al. (2006), showed absence of a conserved filaggrin epitope while retaining epitopes in the N-terminal domain of profilaggrin through immunochemical studies of skin biopsies of both a homozygote and compound heterozygote with the p.Arg501Ter variant. Loss of filaggrin epitopes in cultured keratinocytes from a homozygote were also seen on protein blotting (Smith et al. 2006). Based on the potential impact of truncating variants and application of ACMG criteria, the p.Arg501Ter variant is classified as pathogenic for FLG-related disorders. -
This nonsense variant is found in the last exon of FLG and is therefore predicted to escape nonsense-mediated mRNA decay (NMD). However, nonsense variants located downstream of this variant have been reported as disease-causing variants in the literature (PMID: 20222934). This variant is reported as one of the most common pathogenic FLG variants observed in Caucasian individuals of North/West-European descent with ichthyosis vulgaris (PMID: 16444271). Loss-of-function variation in FLG is an established mechanism of disease (PMID: 27678121, 21428977, 24608987). The c.1501C>T (p.Arg501Ter) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.9% (2653/282652) and in the homozygous state in 21 individuals. Based on the available evidence, the c.1501C>T (p.Arg501Ter) variant is classified as Pathogenic. -
Ichthyosis vulgaris;C1853965:Dermatitis, atopic, 2 Pathogenic:2Other:1
[ACMG/AMP: PVS1, PM3, PP5] This alteration is a null variant in a gene where LOF is a known mechanism of disease [PVS1], is detected in trans with a known pathogenic variant [PM3], was reported as a pathogenic/likely pathogenic alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory) [PP5]. -
Variant reported in multiple GenomeConnect participants by GeneDx. Variant interpreted as Pathogenic and reported, most recently, on 02-22-2022. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -
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Dermatitis, atopic, 2 Pathogenic:2
This variant was identified in a 7 year old male with a history of severe eczema on his legs, arms, face, and trunk since birth. There is no family history of eczema though this variant was inherited from his father. This variant is present in gnomAD at 0.94%, occurring 1.6% in the European Non-Finnish population including 17 homozygotes. -
ACMG classification criteria: PVS1 very strong, PS4 strong, PM3 strong, BS1 strong -
Eczematoid dermatitis Pathogenic:1
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Atopic eczema;C0079584:Ichthyosis vulgaris Pathogenic:1
The R501X nonsense variant has been reported previously as one of the most common pathogenic FLG variants observed in Caucasian individuals of North/West-European descent with ichthyosis vulgaris (Smith et al., 2006). It is also associated with increased risk for atopic dermatitis and asthma (Henderson et al., 2008; Komova et al., 2014; Muller et al., 2009; Gao et al., 2009). -
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