Submissions for variant NM_002016.2(FLG):c.6950_6957del (p.Ala2316_Ser2317insTer)

dbSNP: rs578184315

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484342	SCV000567515	pathogenic	not provided	2024-01-19	criteria provided, single submitter	clinical testing	Observed in the heterozygous or homozygous state in multiple individuals with atopic dermatitis tested at GeneDx and reported in the published literature (PMID: 21039602, 29056476); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 1745 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 29056476, 37200867, 21039602)
3billion, Medical Genetics	RCV001809432	SCV002058195	likely pathogenic	Dermatitis, atopic, 2	2022-01-03	criteria provided, single submitter	clinical testing	Frameshift: predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_S). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000419605, PMID:21039602). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Mendelics	RCV001782963	SCV002516385	pathogenic	Ichthyosis vulgaris	2022-05-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002506166	SCV002813881	likely pathogenic	Dermatitis, atopic, 2; Ichthyosis vulgaris	2022-01-18	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV001782963	SCV004013302	likely pathogenic	Ichthyosis vulgaris	2023-06-15	criteria provided, single submitter	clinical testing	PVS1, PM2
Genome-Nilou Lab	RCV001782963	SCV004050221	likely pathogenic	Ichthyosis vulgaris	2023-04-11	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001782963	SCV005399024	pathogenic	Ichthyosis vulgaris	2024-10-11	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with ichthyosis vulgaris (MIM#146700). (I) 0108 - This gene is associated with both recessive and dominant disease. Biallelic truncating variants tend to result in a more severe condition (PMIDs: 17291859, 30681730). (I) 0112 - The condition associated with this gene has incomplete penetrance. Heterozygous carriers are more likely to be asymptomatic than individuals with biallelic mutations (PMIDs: 17291859, 30681730). (I) 0204 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with at least 1/3 of the protein sequence affected (DECIPHER). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v4) <0.01 (92 heterozygotes, 0 homozygotes). (SP) 0600 - Variant causing truncation results in the loss of downstream annotated filaggrin repeats (DECIPHER). (I) 0701 - Other NMD-escape truncation variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is reported in ClinVar twice as pathogenic and five times as likely pathogenic by clinical laboratories. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV001782963	SCV005416416	likely pathogenic	Ichthyosis vulgaris		criteria provided, single submitter	clinical testing	PVS1_Strong+PS4+PP4
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000484342	SCV001548597	likely pathogenic	not provided		no assertion criteria provided	clinical testing	The FLG p.S2317* variant has been reported in multiple individuals with ichthyosis vulgaris and/or atopic dermatitis (Wong_2018_PMID:29056476; Zhang_2011_PMID:21039602). The variant was identified in dbSNP (ID: rs578184315) and ClinVar (classified as pathogenic by GeneDx). The variant was identified in control databases in 60 of 282722 chromosomes at a frequency of 0.0002122, and was observed at the highest frequency in the East Asian population in 59 of 19906 chromosomes (freq: 0.002964) (Genome Aggregation Database March 6, 2019, v2.1.1). The c.6950_6957delCATCCCAT variant leads to a premature stop codon at position 2317 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the FLG gene are an established mechanism of disease in ichthyosis vulgaris and are the type of variant expected to cause the disorder. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.