ClinVar Miner

Submissions for variant NM_002016.1(FLG):c.2278_2281CAGT[1] (p.Ser761fs) (rs558269137)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 11
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV000017714 SCV000328722 pathogenic Ichthyosis vulgaris no assertion criteria provided clinical testing Our laboratory reported dual molecular diagnoses in FLG (NM_002016.1, c.2282_2285del ) and PACS1 (NM_018026.3, c.607C>T) in one individual with reported features of developmental delay and regression, hypotonia, cryptogenic epilepsy, dystonia, chronic and severe constipation, feeding difficulty, history of skin rash of scalp, face, back, dysmorphic craniofacial features, and thinning of the corpus callosum. The FLG variant has been previously reported in multiple affected patients [e.g. PMID 16444271, 19839980].
Baylor Miraca Genetics Laboratories, RCV000191085 SCV000245481 uncertain significance Dermatitis, atopic, 2; Ichthyosis vulgaris 2015-07-08 criteria provided, single submitter clinical testing 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.
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000017714 SCV000297112 pathogenic Ichthyosis vulgaris 2018-05-03 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000256057 SCV000854988 pathogenic not provided 2018-08-08 criteria provided, single submitter clinical testing
Geisinger Autism and Developmental Medicine Institute,Geisinger Health System RCV000678372 SCV000804438 pathogenic Dermatitis, atopic, 2 2017-10-18 criteria provided, single submitter provider interpretation 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).
GeneDx RCV000256057 SCV000321673 pathogenic not provided 2018-10-25 criteria provided, single submitter clinical testing The c.2282_2285delCAGT deletion is one of the most common pathogenic variants in the FLG gene reported in Caucasian patients of Northern or Western-European descent with ichthyosis vulgaris (Smith et al., 2006). It is also associated with increased risk for atopic dermatitis and asthma (Palmer et al., 2006; Henderson et al., 2008; Komova et al., 2014; Muller et al., 2009; Gao et al., 2009). Consistent with the high prevalence of ichthyosis vulgaris, c.2282_2285delCAGT was also observed with an allele frequency ranging from 0.7% in South Asians to 2.2% in non-Finnish European populations, with multiple homozygous individuals reported (Lek et al., 2016). The c.2282_2285delCAGT change causes a frameshift starting with codon Serine 761, changes this amino acid to a Cysteine residue, and creates a premature Stop codon at position 36 of the new reading frame, denoted p.Ser761CysfsX36. This deletion results in a functional null allele as no processed filaggrin can be biochemically detected in patients with this variant (Smith et al., 2006). Therefore, we interpret c.2282_2285delCAGT as a pathogenic variant.
GenomeConnect, ClinGen RCV000709934 SCV000840291 not provided FLG-Related Disorder no assertion provided phenotyping only 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.
GenomeConnect, ClinGen RCV000017714 SCV000840303 not provided Ichthyosis vulgaris no assertion provided phenotyping only 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000017714 SCV000712217 pathogenic Ichthyosis vulgaris 2018-08-01 criteria provided, single submitter clinical testing 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.
OMIM RCV000017714 SCV000037991 pathogenic Ichthyosis vulgaris 2006-10-01 no assertion criteria provided literature only
OMIM RCV000017715 SCV000037992 risk factor Dermatitis, atopic, 2, susceptibility to 2006-10-01 no assertion criteria provided literature only

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.