FLG S761Shift - GET-Evidence

Curation:
Currentness:

FLG S761Shift

(FLG 761delSinsShift)


Short summary

Based on other severe variants in the same gene, this variant is likely to cause ichthyosis vulgaris when homozygous or compound heterozygous with another severe variant. Some authors report the variant has incomplete dominance, with heterozygotes generally having a very mild phenotype: some palmar hyperlinearity, keratosis pilaris and, in some cases fine scale.

Variant evidence
Computational 3

Other variants in this gene cause this disease, frameshift mutation has severe effect

See Smith FJ et al. 2006 (16444271).

Functional -
Case/Control -
Familial

No familial data for this particular variant, but familial data for other severe variants has very high significance

See Smith FJ et al. 2006 (16444271).

 
Clinical importance
Severity 3

ichthyosis vulgaris

Treatability 1
Penetrance 5

Based on Smith et al’s findings, penetrance is very high

See Smith FJ et al. 2006 (16444271).

 

Impact

Moderate clinical importance, Uncertain pathogenic

(The "moderate clinical importance, uncertain" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern

other

Summary of published research, and additional commentary

 

Allele frequency

  • - @ chr1:150551704: 0.8% (1/126) in GET-Evidence
  • Frequency shown in summary reports: 0.8% (1/126)

Publications
 

Smith FJ, Irvine AD, Terron-Kwiatkowski A, Sandilands A, Campbell LE, Zhao Y, Liao H, Evans AT, Goudie DR, Lewis-Jones S, Arseculeratne G, Munro CS, Sergeant A, O'Regan G, Bale SJ, Compton JG, DiGiovanna JJ, Presland RB, Fleckman P, McLean WH. Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat Genet. 2006 Mar;38(3):337-42. Epub 2006 Jan 29. PubMed PMID: 16444271.

These authors identify two loss-of-function variants in FLG as being associated with icthyosis vulgaris and atopic dermatitis: S2554* and a 4-bp deletion of a “CAGT” sequence that causes a frameshift starting at codon 715.

It is unclear exactly how many families were studied — the paper mentions 15 kindred, but Figure 2 and other mentions describes 7 families. There are also eight sporadic cases, all of which had these mutations (4 hom for R501X, 4 compound het for both). The authors also report very high combined LOD scores for the families: “the maximum combined two-point lod score for families 1-7 (Fig. 2) was 8.11 at theta = 0”.

The authors analyze these variants as having incomplete penetrance, with heterozygotes having a very mild phenotype with palmar hyperlinearity, keratosis pilaris and, in some cases fine scale, while homozygotes had marked presentation of ichtyosis vulgaris with prominent scaling.

The 4bp-deletion in this paper is different from FLG-S761shift (FLG-S761Shift is farther downstream, caused by a deletion of “ACTG”), but it is very similar — S761Shift would be predicted to have a similar effect to the two variants described in this paper.

Genomes
 

huC30901 - CGI sample GS00253-DNA_B01_200_37
het - @ chr1:152285077

 

Other external references
 

    GeneTests
  • GeneTests records for the FLG gene
    FGFR-Related Craniosynostosis
    Kallmann Syndrome
    FGFR1-Related Craniosynostosis
    Kallmann Syndrome 2
    Osteoglophonic Dysplasia
    Pfeiffer Syndrome Type 1, 2 and 3
    Ichthyosis Vulgaris
    www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/FLG

Other in silico analyses
 

  • NBLOSUM100 score = 4
  • GET-Evidence autoscore = 4

Edit history
 

Gene search

"GENE" or "GENE A123C":

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