Submissions for variant NM_002016.2(FLG):c.3321del (p.Gly1109fs)

gnomAD frequency: 0.00029  dbSNP: rs200519781

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000487070	SCV000568701	pathogenic	not provided	2022-05-24	criteria provided, single submitter	clinical testing	One of the most common pathogenic variants in the FLG gene reported in individuals of Asian descent with atopic dermatitis and has been described in Chinese, Japanese, Korean, and Singaporean populations (Nomura et al., 2007; Meng et al., 2014); Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 2953 amino acids are lost and replaced with 12 incorrect amino acids; This variant is associated with the following publications: (PMID: 21923666, 22407025, 22220561, 23152869, 24858702, 23744309, 17291859, 27519469, 27270549, 18521703, 28120571, 29380403, 30021537, 34426522)
Mendelics	RCV000017718	SCV002516391	pathogenic	Ichthyosis vulgaris	2022-05-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000017718	SCV004050257	pathogenic	Ichthyosis vulgaris	2023-04-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000017718	SCV005049880	pathogenic	Ichthyosis vulgaris	2023-12-25	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004787778	SCV005398510	pathogenic	Autosomal dominant ichthyosis vulgaris	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0108 - This gene is known to be associated with both recessive and dominant disease. Biallelic truncating variants generally result in a more severe condition (PMID: 17291859, PMID: 30681730). (N) 0112 - Variants in this gene are known to have reduced penetrance (PMID: 17291859, PMID: 30681730). (N) 0204 - Variant is predicted to result in a truncated protein with more than 1/3 of the protein affected (exon 3 of 3). (P) 0251 - Variant is heterozygous. (N) 0303 - Variant is present in gnomAD v3 >=0.01 for a dominant condition (39 heterozygotes, 1 homozygote). (B) 0701 - Comparable variants have very strong previous evidence for pathogenicity. Many downstream variants also predicted to result in a truncated protein, have been reported in patients with skin conditions (Decipher). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic, and represents one of the most common disease-causing alleles within the Asian population for atopic dermatitis (ClinVar, PMID: 24858702). (P) 1206 - Variant is paternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004796190	SCV005416776	pathogenic	Dermatitis, atopic, 2; Ichthyosis vulgaris		criteria provided, single submitter	clinical testing	PVS1_Strong+PS4+PP4+PS3_Supporting+PP1_Strong
Fulgent Genetics, Fulgent Genetics	RCV004796190	SCV005666048	pathogenic	Dermatitis, atopic, 2; Ichthyosis vulgaris	2024-04-20	criteria provided, single submitter	clinical testing
OMIM	RCV000017718	SCV000037995	pathogenic	Ichthyosis vulgaris	2007-02-01	no assertion criteria provided	literature only
OMIM	RCV000017719	SCV000037996	risk factor	Dermatitis, atopic, 2, susceptibility to	2007-02-01	no assertion criteria provided	literature only
Reproductive Health Research and Development, BGI Genomics	RCV000017718	SCV001142308	pathogenic	Ichthyosis vulgaris	2020-01-06	no assertion criteria provided	curation	NM_002016.1:c.3321delA in the FLG gene has an allele frequency of 0.01 in East Asia subpopulation in the gnomAD database.This variant is predicted to cause loss of normal protein function through protein truncation. The patient's phenotype is highly specific for FLG (PMID: 17291859). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PVS1; PM2_supporting; PP4.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000487070	SCV001953777	pathogenic	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000487070	SCV001963084	pathogenic	not provided		no assertion criteria provided	clinical testing