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Structural Biology Helps Interpret Variants of Uncertain Significance in Genes Causing Endocrine and Metabolic Disorders

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Ittisoponpisan, Sirawit, David, Alessia·2018·Journal of the Endocrine Society
DOI 10.1210/js.2018-00077PMC PMC6041779
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Abstract

Variants of uncertain significance (VUSs) lack sufficient evidence, in terms of statistical power or experimental studies, to allow unequivocal determination of their damaging effect. VUSs are a major burden in performing genetic analysis. Although in silico prediction tools are widely used, their specificity is low, thus urgently calling for methods for prioritizing and characterizing variants. To assess the frequency of VUSs in genes causing endocrine and metabolic disorders, the concordance rate of predictions from different in silico methods, and the added value of three-dimensional protein structure analysis in discerning and prioritizing damaging variants. A total of 12,266 missense variants reported in 641 genes causing endocrine and metabolic disorders were analyzed. Among these, 4123 (33.7%) were VUSs, of which 2010 (48.8%) were predicted to be damaging and 1452 (35.2%) were predicted to be tolerated according to in silico tools. A total of 5383 (87.7%) of 6133 disease-causing variants and 823 (55.8%) of 1474 benign variants were correctly predicted. In silico predictions were noninformative in 5.7%, 14.4%, and 16% of damaging, benign, and VUSs, respectively. A damaging effect on 3D protein structure was present in 240 (30.9%) of predicted damaging and 40 (9.7%) of predicted tolerated VUSs (P < 0.001). An in-depth analysis of nine VUSs occurring in TSHR, LDLR, CASR, and APOE showed that they greatly affect protein stability and are therefore strong candidates for disease. In our dataset, we confirmed the high sensitivity but low specificity of in silico predictions tools. 3D protein structural analysis is a compelling tool for characterizing and prioritizing VUSs and should be a part of genetic variant analysis.

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  • Our findings appear to contrast with previous work reporting that L28P destabilizes ApoE4 in studies using purified recombinant protein.

    “Our findings appear to contrast with previous work by 58,59 ,who reported that L28P destabilizes ApoE4 in studies using purified recombinant protein.”

    From Utilizing a cell culture based novel cellular thermal shift assay to understand the isoform-dependent thermal stability of ApoE variants (2026) · cites this paper as [59]

    The Apolipoprotein E case description (§3.B; page unavailable) reports that ApoE4 Leu28Pro was studied in vitro and that the mutant protein was thermodynamically unstable. It does not specify purified recombinant protein, and it presents the experimental finding as a report from an earlier study rather than its own result. (LLM, conf=0.87)

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Cited by

Sorted by citations

Authors
Ittisoponpisan, S., & David, A.
Affiliations
Imperial College London (GB)
Corresponding author
David, Alessia
ORCID
Venue
Journal of the Endocrine Society
Publisher
The Endocrine Society
Published
2018-06-13
Volume
2
Issue
8
Pages
842-854
ISSN
2472-1972 (ISSN-L)
DOI
10.1210/js.2018-00077
PMC
PMC6041779
OpenAlex
W2808049007
Cited by
8
References
2
Citations by year
2026: 1 · 2024: 1 · 2023: 1 · 2022: 3 · 2021: 1 · 2019: 1
FWCI
0.31
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of the Endocrine Society (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Spiral (Imperial College London) (submittedVersion, cc-by)
Funders
Wellcome Trust
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords
variants of uncertain significance, missense mutations, endocrine disorders, metabolic disorders, in silico prediction tools, protein stability, variant prioritization, TSHR, LDL receptor, calcium-sensing receptor, apolipoprotein E, variant interpretation

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