ClinVar Miner

Submissions for variant NM_002016.1(FLG):c.1501C>T (p.Arg501Ter) (rs61816761)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Division of Human Genetics,Children's Hospital of Philadelphia RCV000017712 SCV000238459 pathogenic Ichthyosis vulgaris 2015-02-03 no assertion criteria provided research This patient is a carrier of a heterozygous pathogenic variant in the FLG gene implicated in causing ichthyosis vulgaris (MIM 146700), as well as being a risk factor for atopic dermatitis (MIM 605803). The FLG variant (c.1501C>T) is a nonsense mutation that is predicted to prematurely truncate the transcript. It has been identified in many patients in the literature and is one of the most common pathogenic mutations identified in this gene in populations of European ancestry (Smith et al. 2006, PMID: 16444271; Weidinger et al. 2007, PMID: 16815158; Palmer et al. 2008, PMID: 16550169). Carriers of this variant have reported to be either asymptomatic with no discernible presentation or be affected by a mild form of icthythosis (Smith et al. 2006, PMID: 16444271) and are at an increased risk for having atopic disease (Palmer et al. 2008, PMID: 16550169).
Fulgent Genetics,Fulgent Genetics RCV000763246 SCV000893883 pathogenic Dermatitis, atopic, 2; Ichthyosis vulgaris 2018-10-31 criteria provided, single submitter clinical testing
Geisinger Autism and Developmental Medicine Institute,Geisinger Health System RCV000678332 SCV000804395 pathogenic Dermatitis, atopic, 2 2018-01-23 criteria provided, single submitter provider interpretation This variant was identified in a 7 year old male with a history of severe eczema on his legs, arms, face, and trunk since birth. There is no family history of eczema though this variant was inherited from his father. This variant is present in gnomAD at 0.94%, occurring 1.6% in the European Non-Finnish population including 17 homozygotes.
GeneDx RCV000255693 SCV000321672 pathogenic not provided 2017-05-31 criteria provided, single submitter clinical testing The R501X nonsense variant has been reported previously as one of the most common pathogenic FLG variants observed in Caucasian individuals of North/West-European descent with ichthyosis vulgaris (Smith et al., 2006). It is also associated with increased risk for atopic dermatitis and asthma (Henderson et al., 2008; Komova et al., 2014; Muller et al., 2009; Gao et al., 2009). R501X introduces a premature termination codon at position 501 of profilaggrin resulting in protein truncation and loss of protein, as no processed filaggrin can be biochemically detected in patients homozygous for this variant (Smith et al., 2006). Individuals who are homozygous for R501X, or compound heterozygous for this nonsense variant with another FLG null allele, typically have a severe form of ichthyosis vulgaris, while those who are heterozygous for R501X display a milder form of ichthyosis (McGrath, et al., 2008; Smith et al., 2006). Consistent with the high prevalence of ichthyosis vulgaris, R501X is observed in 932/66,740 (1.4%) alleles from individuals of non-Finnish European background in the ExAC dataset, with multiple homozygous individuals reported (Lek et al., 2016). We interpret R501X as a pathogenic variant associated with ichthyosis vulgaris.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000017712 SCV000966810 pathogenic Ichthyosis vulgaris 2018-02-06 criteria provided, single submitter clinical testing The p.Arg501X variant in FLG is a well-established pathogenic variant associated with ichthyosis vulgaris (Smith 2006, Rodriguez 2009, Gruber 2011). This varian t has been identified in 0.9% (2595/276976) of total chromosomes, including 19 h omozygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinsti tute.org; dbSNP rs61816761), which is consistent with the reported incidence of ichthyosis vulgaris and the incomplete penetrance in heterozygotes. This nonsens e variant leads to a premature termination codon at position 501, resulting in a n absence of protein as demonstrated by studies in homozygotes and compound hete rozygotes that carried another nonsense variant (Smith 2006, Gruber 2011). Haplo insufficiency of FLG is an established disease mechanism for ichthyosis vulgaris , while biallelic loss of function is associated with a severe phenotype similar to classic lamellar ichthyosis (Smith 2006). In addition, the p.Arg501X and oth er loss-of-function variants in FLG have been associated with increased risk for eczema (OR 2.5-3.7; Henderson 2008, Rodriguez 2009, Schuttelaar 2009, Ziyab 201 2). In summary, the p.Arg501X variant meets criteria to be classified as pathoge nic for ichthyosis vulgaris in an autosomal dominant manner with reduced penetra nce. ACMG/AMP criteria applied: PVS1; PS4; PP1_Strong.
OMIM RCV000017712 SCV000037989 pathogenic Ichthyosis vulgaris 2006-10-01 no assertion criteria provided literature only
OMIM RCV000017713 SCV000037990 risk factor Dermatitis, atopic, 2, susceptibility to 2006-10-01 no assertion criteria provided literature only
Undiagnosed Diseases Network,NIH RCV000787952 SCV000926973 pathogenic Ichthyosis vulgaris; Atopic dermatitis 2018-10-22 criteria provided, single submitter clinical testing The R501X nonsense variant has been reported previously as one of the most common pathogenic FLG variants observed in Caucasian individuals of North/West-European descent with ichthyosis vulgaris (Smith et al., 2006). It is also associated with increased risk for atopic dermatitis and asthma (Henderson et al., 2008; Komova et al., 2014; Muller et al., 2009; Gao et al., 2009).

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