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

Germline classification:: Pathogenic/Likely pathogenic (8 submissions)
Last evaluated:: Jul 19, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000991155.13

Allele description [Variation Report for NM_002016.2(FLG):c.7339C>T (p.Arg2447Ter)]

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

Genes:

CCDST:cervical cancer associated DHX9 suppressive transcript [Gene - HGNC]
FLG:filaggrin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q21.3

Genomic location:

Preferred name:

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

HGVS:

NC_000001.11:g.152307547G>A
NG_016190.1:g.22657C>T
NM_002016.2:c.7339C>TMANE SELECT
NP_002007.1:p.Arg2447Ter
NP_002007.1:p.Arg2447Ter
LRG_1028t1:c.7339C>T
LRG_1028:g.22657C>T
LRG_1028p1:p.Arg2447Ter
NC_000001.10:g.152280023G>A
NM_002016.1:c.7339C>T
p.R2447X

Protein change:

R2447*

Links:

dbSNP: rs138726443

NCBI 1000 Genomes Browser:

rs138726443

Molecular consequence:

NM_002016.2:c.7339C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: Ichthyosis vulgaris
Synonyms:: Ichthyosis simplex; Dominant ichthyosis vulgaris
Identifiers:: MONDO: MONDO:0024304; MedGen: C0079584; OMIM: 146700

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001142306	Reproductive Health Research and Development, BGI Genomics	no assertion criteria provided	Pathogenic (Jan 6, 2020)	germline	curation
SCV001245578	Undiagnosed Diseases Network, NIH	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 10, 2016)	paternal	clinical testing	PubMed (8) [See all records that cite these PMIDs] 17417636, 22995991, 19839980, 19874431, 19785597, 21377035, 26451970, 25741868
SCV001520147	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 19, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001739349	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	no assertion criteria provided	Pathogenic (May 18, 2021)	germline	clinical testing
SCV002028332	Centogene AG - the Rare Disease Company	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 8, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002516380	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2019)	Pathogenic (May 4, 2022)	germline	clinical testing	Citation Link,
SCV003807466	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 19, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004049884	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 11, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
Causasians	paternal	yes	1	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema.

Sandilands A, Terron-Kwiatkowski A, Hull PR, O'Regan GM, Clayton TH, Watson RM, Carrick T, Evans AT, Liao H, Zhao Y, Campbell LE, Schmuth M, Gruber R, Janecke AR, Elias PM, van Steensel MA, Nagtzaam I, van Geel M, Steijlen PM, Munro CS, Bradley DG, Palmer CN, et al.

Nat Genet. 2007 May;39(5):650-4. Epub 2007 Apr 8.

PubMed [citation]

PMID:: 17417636

An informatics approach to analyzing the incidentalome.

Berg JS, Adams M, Nassar N, Bizon C, Lee K, Schmitt CP, Wilhelmsen KC, Evans JP.

Genet Med. 2013 Jan;15(1):36-44. doi: 10.1038/gim.2012.112. Epub 2012 Sep 20.

PubMed [citation]

PMID:: 22995991
PMCID:: PMC3538953

See all PubMed Citations (8)

PMC

Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL.

Genetics in medicine : official journal of the American College of Medical Genetics. 2015 Mar 5; 17(5): 405-424

PMC [article]

PMCID:: PMC4544753
PMID:: 25741868
DOI:: 10.1038/gim.2015.30

Details of each submission

From Reproductive Health Research and Development, BGI Genomics, SCV001142306.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Undiagnosed Diseases Network, NIH, SCV001245578.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Causasians	1	not provided	not provided	clinical testing	PubMed (8)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	paternal	yes	not provided	blood	not provided		1	not provided	1	not provided

From Baylor Genetics, SCV001520147.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics Laboratory, University Hospital Schleswig-Holstein, SCV001739349.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Centogene AG - the Rare Disease Company, SCV002028332.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mendelics, SCV002516380.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein, SCV003807466.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

Description

ACMG classification criteria: PVS1 very strong, PS4 strong, BS1 strong

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Genome-Nilou Lab, SCV004049884.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 19, 2024

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