NM_002016.2(FLG):c.2282_2285del (p.Ser761fs) AND FLG-related disorder

Germline classification:: Pathogenic (3 submissions)
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003398531.8

Allele description [Variation Report for NM_002016.2(FLG):c.2282_2285del (p.Ser761fs)]

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

Genes:

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

Variant type:

Microsatellite

Cytogenetic location:

1q21.3

Genomic location:

Preferred name:

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

HGVS:

NC_000001.11:g.152312601ACTG[1]
NG_016190.1:g.17596CAGT[1]
NM_002016.2:c.2282_2285delMANE SELECT
NP_002007.1:p.Ser761fs
LRG_1028:g.17596CAGT[1]
NC_000001.10:g.152285077ACTG[1]
NC_000001.10:g.152285077_152285080delACTG
NM_002016.1:c.2282_2285delCAGT
NM_002016.2:c.2282_2285delCAGTMANE SELECT
c.2282del4
p.Ser761CysfsX36
p.[Ser761Cysfs]

Protein change:

S761fs

Links:

OMIM: 135940.0002; dbSNP: rs558269137

NCBI 1000 Genomes Browser:

rs558269137

Molecular consequence:

NM_002016.2:c.2282_2285del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: FLG-related disorder
Synonyms:: FLG-related condition; FLG-related disorders
Identifiers:

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Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000840291	GenomeConnect, ClinGen	no classification provided	not provided	maternal, unknown, paternal	phenotyping only
SCV004046166	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004104648	PreventionGenetics, part of Exact Sciences	no assertion criteria provided	Likely pathogenic (Sep 17, 2024)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000840291

GenomeConnect, ClinGen

no classification provided

not provided

maternal, unknown, paternal

phenotyping only

SCV004046166

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004104648

PreventionGenetics, part of Exact Sciences

no assertion criteria provided

Likely pathogenic
(Sep 17, 2024)

germline

clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	paternal	yes	1	not provided	not provided	1	not provided	phenotyping only
not provided	paternal	unknown	1	not provided	not provided	1	not provided	phenotyping only
not provided	maternal	yes	1	not provided	not provided	1	not provided	phenotyping only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	1	not provided	not provided	1	not provided	phenotyping only
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From GenomeConnect, ClinGen, SCV000840291.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	phenotyping only	not provided
2	not provided	1	not provided	not provided	phenotyping only	not provided
3	not provided	1	not provided	not provided	phenotyping only	not provided
4	not provided	1	not provided	not provided	phenotyping only	not provided

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	maternal	yes	1	not provided	not provided		1	not provided	not provided	not provided
2	paternal	yes	1	not provided	validation		1	not provided	not provided	not provided
3	unknown	yes	1	not provided	not provided		1	not provided	not provided	not provided
4	paternal	unknown	1	not provided	validation		1	not provided	not provided	not provided

From Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV004046166.1

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

Description

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.

#	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 PreventionGenetics, part of Exact Sciences, SCV004104648.3

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

Description

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.

#	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

Last Updated: Nov 10, 2024

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