ClinVar Miner

Submissions for variant NM_002016.2(FLG):c.9740C>A (rs150597413)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255466 SCV000322107 pathogenic not provided 2019-01-08 criteria provided, single submitter clinical testing The S3247X variant in the FLG gene has been reported previously as a recurrent pathogenic variant causing ichthyosis vulgaris, while there was no strong association with atopic dermatitis and allergic sensitization (Sandilands et al., 2007; Greisenegger et al., 2010; Ziyab et al., 2012). This variant is predicted to cause loss of normal protein function through protein truncation, and is presumed a functional null allele. Although not present in the homozygous state, the S3247X is observed in 354/126630 (0.28%) alleles from individuals of non-Finnish European background and 400/277112 total alleles in the large population datasets (Lek et al., 2016), consistent with the relatively high prevalence of ichthyosis vulgaris in the population. We interpret S3247X as a pathogenic variant.
Mendelics RCV000986413 SCV001135410 likely pathogenic Ichthyosis vulgaris 2019-05-28 criteria provided, single submitter clinical testing
Johns Hopkins Genomics, Johns Hopkins University RCV001263482 SCV001441564 likely pathogenic Dermatitis, atopic, 2 2020-10-16 criteria provided, single submitter clinical testing This FLG variant (rs150597413) is present in a large population dataset (gnomAD: 417/282786 total alleles; 0.15%; no homozygotes) and has an entry in ClinVar. It is considered one of the more common disease-associated variants in individuals with European ancestry7. 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.9740C>A. Not everyone with a disease-associated variant will develop this disorder, consistent with an increased frequency of this variant in controls from the European population (0.28%). We consider c.9740C>A to be likely pathogenic.
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000255466 SCV001806952 pathogenic not provided no assertion criteria provided clinical testing

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