ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

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Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
27179706 Rimbert et al. (2016) studied eight individuals with familial hypobetalipoproteinemia (FHBL) diagnosis. Targeted next generation sequencing was performed and detected four heterozygous pathogenic nonsense variants that were absent from ExAC database. The first APOB variant (p.Gln845*) was found in 49 years-old female (II:2 of family I) presenting with low LDL-C (20mg/dL). The same variant was inherited in her sons (III:1 and III:2) who also had low LDL-C levels, where son (III:2) exhibited hepatic steatosis without increased liver enzymes; other unaffected family members did not carry the variant. The second APOB variant (p.Gln2571*) was identified in a 41 year-old male (II:1 of family II) presenting with low LDL-C (38 mg/dL), pre-diabetes and liver steatosis (no family study). The third APOB variant (p.Cys2933*) was detected in a 24 year-old female (II:2 in family III) with low LDL-C level (28 mg/dL). Her mother and sister also harbored the same variant and had low LDL-C level. The fourth variant (p.Ser3718*) was seen in an 84 year-old male (1:I of family IV) with low LDL-C level (33mg/dL). His son (II:1) and two grand-children (III:1 and III:2) harbored the same variant and had low level of LDL-C. His son alone also had type 2 diabetes, severe non-alcoholic steatohepatitis with precirrhotic lesions and well-differentiated hepatocellular carcinoma. All four variants generated truncated proteins. The truncated forms of the p.Gln845* (94 kDa) and p.Gln2571* (289 kDa) variants were not visible in plasma, whilst the truncatd forms of the p.Cys2933* (330 kDa) and pSer3718* (418 kDa) variants could be secreted by the liver and lipidated.
1527480 Farese et al. (1992) using SDS-polyacrylamide gel demonstrated heterozygous APOB gene mutation in ten subjects (I-2, I-3, II-2, II-3, II-7, II-9, III-4, III-5, III-6 and III-7) with hypobetalipoproteinemia (FHBL) due to low level of low density lipoprotein (LDL) cholesterol (mean: 49.7 mg/dL) and plasma apoB (mean: 24.5 mg/dL). The mutation was a C to A transversion in exon 26 of APOB gene, hence, converting Ser-3750 (TCA) into a premature stop codon (TAA) (p.Ser3750*). This generated an apoB-83 truncated protein. Interestingly, a newly unique Mse I restriction endonuclease site was found in the APOB gene with the mutation. In the very low density lipoprotein (VLDL) of the affected subjects, the concentration of the apoB-83 level was invariably lower than apoB-100. In the LDL fractions from fasting or postprandial plasma, the apoB-83 level was virtually undetectable.
2843815 Collins et al. (1988) describe two families with truncating variants in APOB and familial hypobetalipoproteinemia. The first proband was an individual ".. under investigation for fat malabsorption. Examination showed no neurological or retinal disease. She had apo-B plasma levels that were less than 2% of normal and > 50% acanthocytes...[B]oth [of the proband's] parents had total plasma cholesterol and apo-B levels below the 5th percentile for their age and sex on each of several occasions on which they were measured (table 1). These are the accepted criteria for diagnosis of heterozygous hypobetalipoproteinaemia. [Each of the parents] had 10% acanthocytes. Plasma HDL levels were normal." The second proband was the mother of a child undergoing investigation for fat malabsorption. Both the mother and child were diagnosed has having hypobetalipoproteinemia, and both were found to be heterozygous for the truncating variant.

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.