ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

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Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
19460837 Whatley et al. studied 467 unrelated patients with proven or putative porphyria. Amongst 123 different HMBS mutations detected by sequencing or qPCR were four multi-exon deletions: exons 3-15, 3-4, 9-15, and 3-11. Article associated with porphyria and hepatocellular carcinoma PMID: 23344888 Sardh et al. studied the incidence of primary liver cancer and clinical characteristics in a cohort of 179 acute porphyria patients above the age of 50 years. Out of 20 acute intermittent porphyria patients with hepatocellular carcinoma (HCC), 18 patients had nonsense, frameshift or splice variants. W198X was the most common variant in this cohort. It was found in 9 patients. The other reported variants were: c.826-2A>G, c.499-1G>A, c.345-2A>G, c.88-2A>G, c.207delT.
12372055 Floderus et al. studied patients with acute intermittent porphyria (AIP). HMBS mutations were detected by DGGE and confirmed by sequencing. A wide mutation spectrum was reported, including: an M1 variant, nonsense variants (in exons 4, 10, and 12), several canonical splice site variants, and several frameshift variants. Article associated with porphyria and hepatocellular carcinoma PMID: 25445397 Xiaoye Schneider-Yin et al. studied 1 patient with two variants in HMBS gene. A 68-year old Swiss female was diagnosed as an asymptomatic carrier of germline mutation p.G111R variant in the HMBS gene was known in her family with AIP. She had never experienced an acute porphyric attack and her urinary PBG concentrations were only slightly above the normal range. She had two solid lesions of 1.7 cm and 2.7 cm, highly suspicious of HCC, in liver. Authors detected a second somatic variant, only in the cancerous tissue i.e. p.L220X in the HMBS gene of this patient, located in trans to the respective germline mutation.
10790212 di Montemuros et al. report seven mutations in eight patients with AIP (biochemically confirmed) detected by DGGE and sequencing: two splicing variants, three frameshift variants, and two nonsense variants.

Evidence for Triplosenstive Phenotype

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.