Submissions for variant NM_002016.2(FLG):c.9947C>G (p.Ser3316Ter)

gnomAD frequency: 0.00246  dbSNP: rs149484917

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000293549	SCV000329592	pathogenic	not provided	2022-03-15	criteria provided, single submitter	clinical testing	Nonsense variant in the C-terminus predicted to result in protein truncation as the last 746 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 25533962, 29791750, 29428354, 31589614, 31365035, 30739909)
Johns Hopkins Genomics, Johns Hopkins University	RCV000991154	SCV001425362	likely pathogenic	Ichthyosis vulgaris	2020-04-01	criteria provided, single submitter	clinical testing	This nonsense variant in FLG is predicted to lead to a premature stop codon (PTC) in the last exon of the gene, likely escaping nonsense?mediated decay and resulting in a truncated protein product. Although the exact function of the C?terminal segment after this PTC is unclear, there are reports of disease?associated nonsense variants located downstream of c.9947C>G. This variant (rs149484917) is present in a large population dataset (gnomAD: 201/282836 total alelles; 0.07%; 5 homozygotes) and is considered one of the more common disease-associated variants in individuals with African ancestry. Not everyone with a disease?associated variant will develop this disorder, consistent with an increased frequency of this variant in controls from the African population (0.78%). This variant has been submitted twice to ClinVar. We consider the c.9947C>G variant to be likely pathogenic.
Mendelics	RCV000991154	SCV002516375	pathogenic	Ichthyosis vulgaris	2022-05-04	criteria provided, single submitter	clinical testing
DASA	RCV000991154	SCV002588791	pathogenic	Ichthyosis vulgaris	2022-11-03	criteria provided, single submitter	clinical testing	The c.9947C>G;p.(Ser3316*) variant creates a premature translational stop signal in the FLG gene. It is expected to result in an absent or disrupted protein product - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 279933; PMID: 29428354, PMID: 29791750) - PS4. The variant is present at low allele frequencies population databases (rs149484917 – gnomAD 0.007107%; ABraOM 0.001708 frequency - https://abraom.ib.usp.br/) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV003137876	SCV003807295	likely pathogenic	Dermatitis, atopic, 2	2022-10-12	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 strong, PM3 moderated
Baylor Genetics	RCV000991154	SCV003835140	pathogenic	Ichthyosis vulgaris	2022-02-25	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000991154	SCV004049861	likely pathogenic	Ichthyosis vulgaris	2023-04-11	criteria provided, single submitter	clinical testing
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV000991154	SCV005397336	pathogenic	Ichthyosis vulgaris	2023-02-22	criteria provided, single submitter	clinical testing	This sequence variant is a single base substitution (C>G) at coding nucleotide 9947 that replaces a serine codon with a premature termition sigl in exon 3 of 3 of the FLG gene. This variant is expected to truncate the FLG encoded profilaggrin protein thereby disrupting C termil domain; loss of the C termil domain prevents processing profilaggrin into filaggrin monomers, generating a loss of function variant (PMID: 17417636, 22071473). This previously reported (ClinVar), well-documented variant is associated with atopic dermatitis (PMID: 29428354, 29791750, 32066784). This variant is present in 201/282836 alleles (0.07%), including 5 homozygotes, in the gnomAD control population dataset. Given the available information, we consider this variant to be pathogenic. ACMG Criteria: PS4, PVS1
Reproductive Health Research and Development, BGI Genomics	RCV000991154	SCV001142305	pathogenic	Ichthyosis vulgaris	2020-01-06	no assertion criteria provided	curation	NM_002016.1: c.9947C>G in the FLG gene has an allele frequency of 0.008 in African subpopulation in the gnomAD database. The c.9947C>G (p.Ser3316*) variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. This variant was reported to be one of the most common pathogenic variants in African population (PMID: 29428354). Taken together, we interprete this variant as Pathogenic/Likely pathogenic.ACMG/AMP criteria applied: PVS1; PM2; PS4.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000293549	SCV001979552	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000293549	SCV001980384	pathogenic	not provided		no assertion criteria provided	clinical testing