VCV000050932.57 - ClinVar

NM_002016.2(FLG):c.7339C>T (p.Arg2447Ter)

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.

(25)

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.7339C>T (p.Arg2447Ter)

Variation ID: 50932 Accession: VCV000050932.57

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q21.3 1: 152307547 (GRCh38) [ NCBI UCSC ] 1: 152280023 (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	Dec 19, 2017	Oct 20, 2024	Mar 25, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_002016.2:c.7339C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002007.1:p.Arg2447Ter	nonsense
NC_000001.11:g.152307547G>A
NC_000001.10:g.152280023G>A
NG_016190.1:g.22657C>T
LRG_1028:g.22657C>T
LRG_1028t1:c.7339C>T	LRG_1028p1:p.Arg2447Ter

... more HGVS ... less HGVS

Protein change

R2447*

Other names

Canonical SPDI

NC_000001.11:152307546:G:A

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.

0.00100 (A)

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

1000 Genomes Project 0.00100

1000 Genomes Project 30x 0.00141

Trans-Omics for Precision Medicine (TOPMed) 0.00288

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00338

Links

ClinGen: CA1104778 dbSNP: rs138726443 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	2	1376
CCDST	-	-	-	GRCh38	-	1453

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.
not provided	Pathogenic/Likely pathogenic (9)	criteria provided, multiple submitters, no conflicts	Feb 2, 2024	RCV000255655.35
Dermatitis, atopic, 2 Ichthyosis vulgaris	Pathogenic (2)	criteria provided, single submitter	Oct 31, 2018	RCV000763245.5
Ichthyosis vulgaris	Pathogenic/Likely pathogenic (9)	criteria provided, multiple submitters, no conflicts	Jan 13, 2024	RCV000991155.16
Dermatitis, atopic, 2	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Mar 25, 2024	RCV001253562.5
FLG-related disorder	Pathogenic (1)	criteria provided, single submitter	Sep 2, 2021	RCV004549477.2
Dermatitis, atopic	Pathogenic (1)	criteria provided, single submitter	-	RCV004576917.2

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 (Nov 10, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ichthyosis vulgaris (Autosomal dominant inheritance) Affected status: yes Allele origin: paternal	Undiagnosed Diseases Network, NIH Accession: SCV001245578.1 First in ClinVar: May 12, 2020 Last updated: May 12, 2020	Publications: PubMed (8) PubMed: 25741868‚ 17417636‚ 22995991‚ 19839980‚ 19874431‚ 19785597‚ 21377035‚ 26451970 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30 Number of individuals with the variant: 1 Clinical Features: Respiratory infections in early life (present) , Recurrent skin infections (present) , Primary Caesarian section (present) , Maternal fever in pregnancy (present) , Keratoconjunctivitis sicca … (more) Respiratory infections in early life (present) , Recurrent skin infections (present) , Primary Caesarian section (present) , Maternal fever in pregnancy (present) , Keratoconjunctivitis sicca (present) , Increased IgE level (present) , Esophagitis (present) , Eosinophilia (present) , Eczema (present) , Caesarian section (present) , Asthma (present) , Allergy (present) , Allergic rhinitis (present) , Abnormal delivery (present) , Abdominal pain (present) (less) Age: 10-19 years Sex: male Ethnicity/Population group: Causasians Tissue: blood Testing laboratory: Baylor Genetics Date variant was reported to submitter: 2016-11-10 Testing laboratory interpretation: Pathogenic
Pathogenic (Jan 06, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Dermatitis, atopic, 2 Affected status: yes Allele origin: germline	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001429342.1 First in ClinVar: Aug 17, 2020 Last updated: Aug 17, 2020	Number of individuals with the variant: 1
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001447058.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Asthma (present) , Allergic rhinitis (present) , Cough (present) , Gastroesophageal reflux (present) Sex: male
Pathogenic (Jun 22, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000321675.6 First in ClinVar: Oct 09, 2016 Last updated: Dec 19, 2017	Comment: Recurrent variant that has been reported multiple times in association with ichthyosis vulgaris and atopic dermatitis as one of the more prevalent FLG pathogenic variants … (more) Recurrent variant that has been reported multiple times in association with ichthyosis vulgaris and atopic dermatitis as one of the more prevalent FLG pathogenic variants among Northern Europeans (Sandilands et al., 2007; Greisenegger et al., 2010; Gimalova et al., 2016); Nonsense variant in the C-terminus predicted to result in protein truncation; other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 26451970, 17417636, 31365035, 19874431, 19839980, 22951058, 19785597, 22995991, 21377035, 28213896, 27363669, 29068602, 29428354, 29054605, 30665703, 31589614, 33144682) (less)
Pathogenic (Sep 02, 2021)	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020) Method: clinical testing	FLG-related disorders Affected status: unknown Allele origin: unknown	Illumina Laboratory Services, Illumina Accession: SCV002034814.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021	Publications: PubMed (4) PubMed: 18396323‚ 19874431‚ 27363669‚ 31637781 Comment: The FLG c.7339C>T (p.Arg2447Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. Across a selection of … (more) The FLG c.7339C>T (p.Arg2447Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. Across a selection of the available literature, the p.Arg2447Ter variant has been identified in a heterozygous state in at least 32 individuals with atopic dermatitis (Weidinger et al. 2008; Greisenegger et al. 2009; Gimalova et al. 2016; González-Tarancon et al. 2020). The p.Arg2447Ter variant was also reported in a heterozygous state in 28 matched population control subjects, and is reported at a frequency of 0.006488 in the European (Finnish) population of the Genome Aggregation Database (version 2.1.1). This allele frequency is high but is consistent with high prevalence and variable severity seen in affected individuals. Based on the evidence, the p.Arg2447Ter variant is classified as pathogenic for FLG-related disorders. (less)
Pathogenic (Aug 20, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Dermatitis, atopic, 2 Affected status: unknown Allele origin: inherited	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn Accession: SCV002103011.1 First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022	Comment: PVS1, PS2, BS2
Pathogenic (May 04, 2022)	criteria provided, single submitter (Mendelics Assertion Criteria 2019) Method: clinical testing	Ichthyosis vulgaris Affected status: unknown Allele origin: germline	Mendelics Accession: SCV002516380.1 First in ClinVar: May 28, 2022 Last updated: May 28, 2022
Pathogenic (Aug 19, 2022)	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: SCV003807466.1 First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023	Comment: ACMG classification criteria: PVS1 very strong, PS4 strong, BS1 strong Number of individuals with the variant: 1 Clinical Features: Eosinophilia (present) , Asthma (present) , Abnormal facial shape (present) , Increased circulating IgE concentration (present) , Eczematoid dermatitis (present) , Cellulitis (present) Geographic origin: Brazil Method: Paired-end whole-genome sequencing
Likely pathogenic (Aug 15, 2023)	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: SCV004025134.1 First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023
Pathogenic (Mar 07, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV004026281.1 First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023	Comment: PVS1, PS3
Likely pathogenic (Apr 11, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ichthyosis vulgaris Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV004049884.1 First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023
Pathogenic (Mar 25, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Dermatitis, atopic, 2 Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004806389.1 First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024
Pathogenic (Nov 07, 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: SCV005045024.1 First in ClinVar: May 26, 2024 Last updated: May 26, 2024	Comment: The FLG c.7339C>T (p.Arg2447Ter) variant has been reported in several individuals affected with ichthyosis vulgaris and atopic dermatitis and is reported in a compound heterozygous … (more) The FLG c.7339C>T (p.Arg2447Ter) variant has been reported in several individuals affected with ichthyosis vulgaris and atopic dermatitis and is reported in a compound heterozygous state with a pathogenic or likely pathogenic variant in at least at least one individual, and in a heterozygous state in over 100 individuals (Gonz√°lez-Taranc√≥n R et al., PMID: 31637781; Greisenegger E et al., PMID: 19874431; Gruber R et al., PMID: 19785597; Sandilands A et al., PMID: 17417636; Schuttelaar M et al., PMID: 19839980; Timmerman JG et al., PMID: 26451970; Weidinger S et al., PMID: 18396323). The highest population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 0.65% in the European (non-Finnish) population. This variant has been reported in the ClinVar database as a pathogenic variant by 18 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. (less)
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: SCV001520147.3 First in ClinVar: Mar 22, 2021 Last updated: Jun 09, 2024
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Dermatitis, atopic Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV005060980.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024	Comment: The observed stop gained variant c.7339C>T(p.Arg2447Ter) in FLG gene has been reported in heterozygous state in multiple individuals with Ichthyosis vulgaris and atopic dermatitis. This … (more) The observed stop gained variant c.7339C>T(p.Arg2447Ter) in FLG gene has been reported in heterozygous state in multiple individuals with Ichthyosis vulgaris and atopic dermatitis. This recurrent variant is one of the more prevalent FLG pathogenic variants among Northern Europeans (González-Tarancón R, et al., 2020, Gimalova et al., 2016). The c.7339C>T variant has 0.2% allele frequency in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing (González-Tarancón R, et al., 2020). For these reasons, this variant has been classified as Pathogenic. (less) Clinical Features: Abnormality of the skin (present)
Pathogenic (Dec 01, 2022)	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: SCV001245944.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: FLG: PVS1, PP1, PP4, PS4:Supporting Number of individuals with the variant: 9
Pathogenic (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ichthyosis vulgaris Dermatitis, atopic, 2 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000893882.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Jun 08, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ichthyosis vulgaris Affected status: yes Allele origin: germline	Centogene AG - the Rare Disease Company Accession: SCV002028332.1 First in ClinVar: Dec 04, 2021 Last updated: Dec 04, 2021
Likely pathogenic (Feb 02, 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: SCV005328414.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024
Pathogenic (Jan 06, 2020)	no assertion criteria provided Method: curation	Ichthyosis vulgaris Affected status: unknown Allele origin: germline	Reproductive Health Research and Development, BGI Genomics Accession: SCV001142306.1 First in ClinVar: Jan 12, 2020 Last updated: Jan 12, 2020	Comment: NM_002016.1:c.7339C>T in the FLG gene has an allele frequency of 0.006 in European(non-Finnish) subpopulation in the gnomAD database.This variant is predicted to cause loss of … (more) NM_002016.1:c.7339C>T in the FLG gene has an allele frequency of 0.006 in European(non-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 has been reported multiple times in association with ichthyosis vulgaris and atopic dermatitis as one of the most prevalent FLG pathogenic variants among Northern Europeans (PMID: 17417636; 19874431; 27363669). Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP criteria applied: PVS1; PM2; PS4. (less)
Pathogenic (May 18, 2021)	no assertion criteria provided Method: clinical testing	Ichthyosis vulgaris Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein Accession: SCV001739349.1 First in ClinVar: Jul 07, 2021 Last updated: Jul 07, 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: SCV001744160.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
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: SCV002037623.1 First in ClinVar: Dec 21, 2021 Last updated: Dec 21, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001952404.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
not provided (-)	no classification provided Method: phenotyping only	Ichthyosis vulgaris Dermatitis, atopic, 2 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: yes Allele origin: maternal	GenomeConnect, ClinGen Accession: SCV002818406.2 First in ClinVar: Jan 07, 2023 Last updated: Jun 17, 2024	Comment: Variant classified as Pathogenic and reported on 09-09-2020 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided … (more) Variant classified as Pathogenic and reported on 09-09-2020 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. (less) Clinical Features: Abnormal delivery (present) , Pregnancy history (present) , Overgrowth (present) , Obesity (present) , Abnormality of coordination (present) , Seizure (present) Indication for testing: Diagnostic Age: 0-9 years Sex: female Method: Exome Sequencing Testing laboratory: GeneDx Date variant was reported to submitter: 2020-09-09 Testing laboratory interpretation: Pathogenic
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Comment:

Recurrent variant that has been reported multiple times in association with ichthyosis vulgaris and atopic dermatitis as one of the more prevalent FLG pathogenic variants among Northern Europeans (Sandilands et al., 2007; Greisenegger et al., 2010; Gimalova et al., 2016); Nonsense variant in the C-terminus predicted to result in protein truncation; other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 26451970, 17417636, 31365035, 19874431, 19839980, 22951058, 19785597, 22995991, 21377035, 28213896, 27363669, 29068602, 29428354, 29054605, 30665703, 31589614, 33144682)

Comment:

The FLG c.7339C>T (p.Arg2447Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. Across a selection of the available literature, the p.Arg2447Ter variant has been identified in a heterozygous state in at least 32 individuals with atopic dermatitis (Weidinger et al. 2008; Greisenegger et al. 2009; Gimalova et al. 2016; González-Tarancon et al. 2020). The p.Arg2447Ter variant was also reported in a heterozygous state in 28 matched population control subjects, and is reported at a frequency of 0.006488 in the European (Finnish) population of the Genome Aggregation Database (version 2.1.1). This allele frequency is high but is consistent with high prevalence and variable severity seen in affected individuals. Based on the evidence, the p.Arg2447Ter variant is classified as pathogenic for FLG-related disorders.

Comment:

The FLG c.7339C>T (p.Arg2447Ter) variant has been reported in several individuals affected with ichthyosis vulgaris and atopic dermatitis and is reported in a compound heterozygous state with a pathogenic or likely pathogenic variant in at least at least one individual, and in a heterozygous state in over 100 individuals (Gonz√°lez-Taranc√≥n R et al., PMID: 31637781; Greisenegger E et al., PMID: 19874431; Gruber R et al., PMID: 19785597; Sandilands A et al., PMID: 17417636; Schuttelaar M et al., PMID: 19839980; Timmerman JG et al., PMID: 26451970; Weidinger S et al., PMID: 18396323). The highest population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 0.65% in the European (non-Finnish) population. This variant has been reported in the ClinVar database as a pathogenic variant by 18 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.

Comment:

The observed stop gained variant c.7339C>T(p.Arg2447Ter) in FLG gene has been reported in heterozygous state in multiple individuals with Ichthyosis vulgaris and atopic dermatitis. This recurrent variant is one of the more prevalent FLG pathogenic variants among Northern Europeans (González-Tarancón R, et al., 2020, Gimalova et al., 2016). The c.7339C>T variant has 0.2% allele frequency in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing (González-Tarancón R, et al., 2020). For these reasons, this variant has been classified as Pathogenic.

Comment:

NM_002016.1:c.7339C>T in the FLG gene has an allele frequency of 0.006 in European(non-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 has been reported multiple times in association with ichthyosis vulgaris and atopic dermatitis as one of the most prevalent FLG pathogenic variants among Northern Europeans (PMID: 17417636; 19874431; 27363669). Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP criteria applied: PVS1; PM2; PS4.

Comment:

Variant classified as Pathogenic and reported on 09-09-2020 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.

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
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
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
Contact dermatitis in the construction industry: the role of filaggrin loss-of-function mutations.	Timmerman JG	The British journal of dermatology	2016	PMID: 26451970
An informatics approach to analyzing the incidentalome.	Berg JS	Genetics in medicine : official journal of the American College of Medical Genetics	2013	PMID: 22995991
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
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
Increased pachyonychia congenita severity in patients with concurrent keratin and filaggrin mutations.	Gruber R	The British journal of dermatology	2009	PMID: 19785597
Filaggrin mutations, atopic eczema, hay fever, and asthma in children.	Weidinger S	The Journal of allergy and clinical immunology	2008	PMID: 18396323
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

Text-mined citations for rs138726443 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_002016.2(FLG):c.7339C>T (p.Arg2447Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs138726443 ...