ClinVar Miner

Submissions for variant NM_002016.2(FLG):c.9947C>G (rs149484917)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000293549 SCV000329592 pathogenic not provided 2018-06-21 criteria provided, single submitter clinical testing The S3316X pathogenic variant in the FLG gene has been observed previously in a patient with reported eczema, who was ascertained and tested by exome sequencing for developmental delay (Fitzgerald et al., 2015). This variant is predicted to cause loss of normal protein function through protein truncation with loss of the last 746 amino acid residues. The S3316X variant is observed in 187/24000 (0.78%) alleles, including five homozygous individuals, from individuals of African background, in large population cohorts, consistent with the notion that S3316X might be a relatively common disease allele in this population group (Lek et al., 2016). We interpret S3316X as a pathogenic variant.
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.
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.

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