Submissions for variant NM_002016.2(FLG):c.7031C>G (p.Ser2344Ter)

gnomAD frequency: 0.00004  dbSNP: rs372754256

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000622390	SCV000742835	pathogenic	Inborn genetic diseases	2017-11-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000760852	SCV000890748	pathogenic	not provided	2024-11-08	criteria provided, single submitter	clinical testing	Identified in individuals with atopic dermatitis; several of these individuals also had other variants in the FLG gene (PMID: 37067103, 29056476); Nonsense variant predicted to result in protein truncation, as the last 1718 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: 37200867, 37067103, 29056476)
Mendelics	RCV001783120	SCV002516384	pathogenic	Ichthyosis vulgaris	2022-05-04	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV001783120	SCV002521545	likely pathogenic	Ichthyosis vulgaris	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.047%). Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000522001 / PMID: 29056476). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Genome-Nilou Lab	RCV001783120	SCV004049890	likely pathogenic	Ichthyosis vulgaris	2023-04-11	criteria provided, single submitter	clinical testing
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV004783825	SCV005397406	likely pathogenic	Dermatitis, atopic, 2	2022-07-12	criteria provided, single submitter	clinical testing	This sequence variant is a single nucleotide substitution (C>G) at coding position 7031 of the FLG gene that generates a premature stop codon at serine 2344 of the FLG protein. This variant is predicted to generate a non-functiol allele through either the expression of a truncated protein or by nonsense mediated decay. This variant was observed by NGS and confirmed with Sanger sequencing. However, due to the presence of several large homologous repeats within FLG, the termition codon may not reside in the exact location listed above. This is a previously reported variant (ClinVar) that has been observed in the literature in individuals with atopic dermatitis (PMID: 29056476). This variant is present in control population datasets (gnomAD database 117 of 250512 alleles or 0.047%). Because haploinsufficiency is a known mechanism of disease for FLG, we consider this variant to be likely pathogenic. ACMG Criteria: PP3, PVS1
Neuberg Centre For Genomic Medicine, NCGM	RCV001783120	SCV005401042	likely pathogenic	Ichthyosis vulgaris		criteria provided, single submitter	clinical testing	The stop gained variant c.7031C>G (p.Ser2344Ter) in the FLG gene has been reported in an individual affected with Ichthyosis vulgaris (Wong et al., 2018). The variant has 0.04% allele frequency in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic/ Likely pathogenic. However, study on multiple affected individuals and functional studies on the pathogenicity of the variant is unavailable. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease-causing (Smith et al., 2006). For these reasons, this variant has been classified as Likely Pathogenic.