ClinGen Dosage Sensitivity Curation Page

Gene Information

• id: ISCA-16608
• Date last evaluated: 2013-02-28
• Issue Type: ClinGen Gene Curation
• Gene type: protein-coding
• Entrez Gene: https://www.ncbi.nlm.nih.gov/gene/79719
• OMIM: https://www.omim.org/entry/614888

Location Information

• 15q23
• GRCh37/hg19 chr15: 67,493,013-67,547,536

Evidence for Loss Phenotypes

• Loss of function score: 3
• Strength of Evidence: Sufficient evidence for dosage pathogenicity
• Haploinsufficiency phenotype: PALMOPLANTAR KERATODERMA, PUNCTATE TYPE IA; PPKP1A

Evidence for loss of function phenotype

PubMed ID	Description
23064416	Pohler et al 2012: 18 families with autosomal dominant punctate palmoplantar keratoderma were shown to have loss of function mutations (variety of nonsense, frameshift and splicing mutations) in AAGAB. The skin findings were variable, with both mild and severe manifestations and onset in the first or second decade of life. Authors of this paper state that anecdotal association of AAGAB mutations with neoplasia has not been proven and may be coincidental.
23000146	Giel et al 2012: 2 novel nonsense mutations described in 3 independent pedigrees segregating autosomal dominant punctate palmoplantar keratoderma. Both intra- and inter-familial phenotypic heterogeneity was described.

• Loss of function phenotype comments: Punctate palmoplantar keratoderma (PPKP) type I (PPKP1), also called keratosis punctate palmoplantaris type Buschke-Fischer-Brauer, is a rare hereditary skin disease of the palms and soles and is characterized by multiple hyperkeratotic papules and central indentation irregularly distributed on the palms and soles. This disorder was recently found to be associated with haploinsufficiency of AAGAB.

Evidence for Triplosenstive Phenotype

• Triplosensitivity score: 0
• Strength of Evidence: No evidence for dosage pathogenicity

• Triplosensitivity phenotype comment: No focal duplications were found at the time of this review.

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.