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Variant of unknown significance

MedGen UID:
458608
•Concept ID:
C2986382
•
Finding
Synonyms: Uncertain Significance; Variant of Undetermined Significance; Variant of Unknown Significance

Professional guidelines

PubMed

Genetic Counseling, Testing, and Family Communication Into Survivorship After Diagnosis of Breast Cancer.
Katz SJ, Abrahamse P, Furgal A, Hodan R, Tocco RS, Ward KC, Hamilton AS, Wallner LP, Kurian AW
J Clin Oncol 2024 Sep 10;42(26):3123-3129. Epub 2024 Jul 15 doi: 10.1200/JCO.24.00122. PMID: 39008790Free PMC Article
Clinical and ECG variables to predict the outcome of genetic testing in hypertrophic cardiomyopathy.
Robyns T, Breckpot J, Nuyens D, Vandenberk B, Corveleyn A, Kuiperi C, Van Aelst L, Van Cleemput J, Willems R
Eur J Med Genet 2020 Mar;63(3):103754. Epub 2019 Sep 9 doi: 10.1016/j.ejmg.2019.103754. PMID: 31513939
Sudden death and cardiac arrest without phenotype: the utility of genetic testing.
Wijeyeratne YD, Behr ER
Trends Cardiovasc Med 2017 Apr;27(3):207-213. Epub 2016 Aug 31 doi: 10.1016/j.tcm.2016.08.010. PMID: 27692676

Recent clinical studies

Etiology

Rapid Whole-Genomic Sequencing and a Targeted Neonatal Gene Panel in Infants With a Suspected Genetic Disorder.
Maron JL, Kingsmore S, Gelb BD, Vockley J, Wigby K, Bragg J, Stroustrup A, Poindexter B, Suhrie K, Kim JH, Diacovo T, Powell CM, Trembath A, Guidugli L, Ellsworth KA, Reed D, Kurfiss A, Breeze JL, Trinquart L, Davis JM
JAMA 2023 Jul 11;330(2):161-169. doi: 10.1001/jama.2023.9350. PMID: 37432431Free PMC Article
Clinical and Molecular Characterization of POLE Mutations as Predictive Biomarkers of Response to Immune Checkpoint Inhibitors in Advanced Cancers.
Garmezy B, Gheeya J, Lin HY, Huang Y, Kim T, Jiang X, Thein KZ, Pilié PG, Zeineddine F, Wang W, Shaw KR, Rodon J, Shen JP, Yuan Y, Meric-Bernstam F, Chen K, Yap TA
JCO Precis Oncol 2022 Feb;6:e2100267. doi: 10.1200/PO.21.00267. PMID: 35108036Free PMC Article
Successful application of genome sequencing in a diagnostic setting: 1007 index cases from a clinically heterogeneous cohort.
Bertoli-Avella AM, Beetz C, Ameziane N, Rocha ME, Guatibonza P, Pereira C, Calvo M, Herrera-Ordonez N, Segura-Castel M, Diego-Alvarez D, Zawada M, Kandaswamy KK, Werber M, Paknia O, Zielske S, Ugrinovski D, Warnack G, Kampe K, Iurașcu MI, Cozma C, Vogel F, Alhashem A, Hertecant J, Al-Shamsi AM, Alswaid AF, Eyaid W, Al Mutairi F, Alfares A, Albalwi MA, Alfadhel M, Al-Sannaa NA, Reardon W, Alanay Y, Rolfs A, Bauer P
Eur J Hum Genet 2021 Jan;29(1):141-153. Epub 2020 Aug 28 doi: 10.1038/s41431-020-00713-9. PMID: 32860008Free PMC Article
Clinical and ECG variables to predict the outcome of genetic testing in hypertrophic cardiomyopathy.
Robyns T, Breckpot J, Nuyens D, Vandenberk B, Corveleyn A, Kuiperi C, Van Aelst L, Van Cleemput J, Willems R
Eur J Med Genet 2020 Mar;63(3):103754. Epub 2019 Sep 9 doi: 10.1016/j.ejmg.2019.103754. PMID: 31513939
Burosumab versus conventional therapy in children with X-linked hypophosphataemia: a randomised, active-controlled, open-label, phase 3 trial.
Imel EA, Glorieux FH, Whyte MP, Munns CF, Ward LM, Nilsson O, Simmons JH, Padidela R, Namba N, Cheong HI, Pitukcheewanont P, Sochett E, Högler W, Muroya K, Tanaka H, Gottesman GS, Biggin A, Perwad F, Mao M, Chen CY, Skrinar A, San Martin J, Portale AA
Lancet 2019 Jun 15;393(10189):2416-2427. Epub 2019 May 16 doi: 10.1016/S0140-6736(19)30654-3. PMID: 31104833Free PMC Article

Diagnosis

Rapid Whole-Genomic Sequencing and a Targeted Neonatal Gene Panel in Infants With a Suspected Genetic Disorder.
Maron JL, Kingsmore S, Gelb BD, Vockley J, Wigby K, Bragg J, Stroustrup A, Poindexter B, Suhrie K, Kim JH, Diacovo T, Powell CM, Trembath A, Guidugli L, Ellsworth KA, Reed D, Kurfiss A, Breeze JL, Trinquart L, Davis JM
JAMA 2023 Jul 11;330(2):161-169. doi: 10.1001/jama.2023.9350. PMID: 37432431Free PMC Article
Resistance to Thyroid Hormone Beta: A Focused Review.
Pappa T, Refetoff S
Front Endocrinol (Lausanne) 2021;12:656551. Epub 2021 Mar 31 doi: 10.3389/fendo.2021.656551. PMID: 33868182Free PMC Article
Successful application of genome sequencing in a diagnostic setting: 1007 index cases from a clinically heterogeneous cohort.
Bertoli-Avella AM, Beetz C, Ameziane N, Rocha ME, Guatibonza P, Pereira C, Calvo M, Herrera-Ordonez N, Segura-Castel M, Diego-Alvarez D, Zawada M, Kandaswamy KK, Werber M, Paknia O, Zielske S, Ugrinovski D, Warnack G, Kampe K, Iurașcu MI, Cozma C, Vogel F, Alhashem A, Hertecant J, Al-Shamsi AM, Alswaid AF, Eyaid W, Al Mutairi F, Alfares A, Albalwi MA, Alfadhel M, Al-Sannaa NA, Reardon W, Alanay Y, Rolfs A, Bauer P
Eur J Hum Genet 2021 Jan;29(1):141-153. Epub 2020 Aug 28 doi: 10.1038/s41431-020-00713-9. PMID: 32860008Free PMC Article
Burosumab versus conventional therapy in children with X-linked hypophosphataemia: a randomised, active-controlled, open-label, phase 3 trial.
Imel EA, Glorieux FH, Whyte MP, Munns CF, Ward LM, Nilsson O, Simmons JH, Padidela R, Namba N, Cheong HI, Pitukcheewanont P, Sochett E, Högler W, Muroya K, Tanaka H, Gottesman GS, Biggin A, Perwad F, Mao M, Chen CY, Skrinar A, San Martin J, Portale AA
Lancet 2019 Jun 15;393(10189):2416-2427. Epub 2019 May 16 doi: 10.1016/S0140-6736(19)30654-3. PMID: 31104833Free PMC Article
Clinical exome sequencing: results from 2819 samples reflecting 1000 families.
Trujillano D, Bertoli-Avella AM, Kumar Kandaswamy K, Weiss ME, Köster J, Marais A, Paknia O, Schröder R, Garcia-Aznar JM, Werber M, Brandau O, Calvo Del Castillo M, Baldi C, Wessel K, Kishore S, Nahavandi N, Eyaid W, Al Rifai MT, Al-Rumayyan A, Al-Twaijri W, Alothaim A, Alhashem A, Al-Sannaa N, Al-Balwi M, Alfadhel M, Rolfs A, Abou Jamra R
Eur J Hum Genet 2017 Feb;25(2):176-182. Epub 2016 Nov 16 doi: 10.1038/ejhg.2016.146. PMID: 27848944Free PMC Article

Therapy

Targeting complement dysregulation: eculizumab in scleroderma renal crisis management-a case-based review.
Toker Dincer Z, Dincer MT, Sen G, Ugurlu S, Seyahi N, Seyahi E
Rheumatol Int 2024 Dec;44(12):3135-3140. Epub 2024 Aug 15 doi: 10.1007/s00296-024-05689-z. PMID: 39147912
Whole exome sequencing in fetuses with isolated increased nuchal translucency: a systematic review and meta-analysis.
Di Girolamo R, Rizzo G, Khalil A, Alameddine S, Lisi G, Liberati M, Novelli A, D'Antonio F
J Matern Fetal Neonatal Med 2023 Dec;36(1):2193285. doi: 10.1080/14767058.2023.2193285. PMID: 37019452
Audit of Molecular Mechanisms of Primary and Secondary Resistance to Various Generations of Tyrosine Kinase Inhibitors in Known Epidermal Growth Factor Receptor-Mutant Non-small Cell Lung Cancer Patients in a Tertiary Centre.
Suryavanshi M, Jaipuria J, Mattoo S, Dhandha S, Khatri M
Clin Oncol (R Coll Radiol) 2022 Nov;34(11):e451-e462. Epub 2022 Jul 7 doi: 10.1016/j.clon.2022.06.003. PMID: 35810049
Relevance of pathogenicity prediction tools in human RYR1 variants of unknown significance.
Hoppe K, Jurkat-Rott K, Kranepuhl S, Wearing S, Heiderich S, Merlak S, Klingler W
Sci Rep 2021 Feb 9;11(1):3445. doi: 10.1038/s41598-021-82024-7. PMID: 33564012Free PMC Article
Burosumab versus conventional therapy in children with X-linked hypophosphataemia: a randomised, active-controlled, open-label, phase 3 trial.
Imel EA, Glorieux FH, Whyte MP, Munns CF, Ward LM, Nilsson O, Simmons JH, Padidela R, Namba N, Cheong HI, Pitukcheewanont P, Sochett E, Högler W, Muroya K, Tanaka H, Gottesman GS, Biggin A, Perwad F, Mao M, Chen CY, Skrinar A, San Martin J, Portale AA
Lancet 2019 Jun 15;393(10189):2416-2427. Epub 2019 May 16 doi: 10.1016/S0140-6736(19)30654-3. PMID: 31104833Free PMC Article

Prognosis

Towards more accurate pharmacogenomic variant effect predictions.
Park Y, Lauschke VM
Pharmacogenomics 2023 Nov;24(16):841-844. Epub 2023 Oct 17 doi: 10.2217/pgs-2023-0187. PMID: 37846582
Clinical and Molecular Characterization of POLE Mutations as Predictive Biomarkers of Response to Immune Checkpoint Inhibitors in Advanced Cancers.
Garmezy B, Gheeya J, Lin HY, Huang Y, Kim T, Jiang X, Thein KZ, Pilié PG, Zeineddine F, Wang W, Shaw KR, Rodon J, Shen JP, Yuan Y, Meric-Bernstam F, Chen K, Yap TA
JCO Precis Oncol 2022 Feb;6:e2100267. doi: 10.1200/PO.21.00267. PMID: 35108036Free PMC Article
Mutations of BRCA1/2 Genes in the West of Turkey and Genotype-Phenotype Correlations.
Gun-Bilgic D, Aydin-Gumus A, Bilgic A, Cam FS
Clin Lab 2022 Jan 1;68(1) doi: 10.7754/Clin.Lab.2021.210425. PMID: 35023674
Stepwise ABC system for classification of any type of genetic variant.
Houge G, Laner A, Cirak S, de Leeuw N, Scheffer H, den Dunnen JT
Eur J Hum Genet 2022 Feb;30(2):150-159. Epub 2021 May 13 doi: 10.1038/s41431-021-00903-z. PMID: 33981013Free PMC Article
Clinical and ECG variables to predict the outcome of genetic testing in hypertrophic cardiomyopathy.
Robyns T, Breckpot J, Nuyens D, Vandenberk B, Corveleyn A, Kuiperi C, Van Aelst L, Van Cleemput J, Willems R
Eur J Med Genet 2020 Mar;63(3):103754. Epub 2019 Sep 9 doi: 10.1016/j.ejmg.2019.103754. PMID: 31513939

Clinical prediction guides

Towards more accurate pharmacogenomic variant effect predictions.
Park Y, Lauschke VM
Pharmacogenomics 2023 Nov;24(16):841-844. Epub 2023 Oct 17 doi: 10.2217/pgs-2023-0187. PMID: 37846582
Clinical and Molecular Characterization of POLE Mutations as Predictive Biomarkers of Response to Immune Checkpoint Inhibitors in Advanced Cancers.
Garmezy B, Gheeya J, Lin HY, Huang Y, Kim T, Jiang X, Thein KZ, Pilié PG, Zeineddine F, Wang W, Shaw KR, Rodon J, Shen JP, Yuan Y, Meric-Bernstam F, Chen K, Yap TA
JCO Precis Oncol 2022 Feb;6:e2100267. doi: 10.1200/PO.21.00267. PMID: 35108036Free PMC Article
Clinical and ECG variables to predict the outcome of genetic testing in hypertrophic cardiomyopathy.
Robyns T, Breckpot J, Nuyens D, Vandenberk B, Corveleyn A, Kuiperi C, Van Aelst L, Van Cleemput J, Willems R
Eur J Med Genet 2020 Mar;63(3):103754. Epub 2019 Sep 9 doi: 10.1016/j.ejmg.2019.103754. PMID: 31513939
Burosumab versus conventional therapy in children with X-linked hypophosphataemia: a randomised, active-controlled, open-label, phase 3 trial.
Imel EA, Glorieux FH, Whyte MP, Munns CF, Ward LM, Nilsson O, Simmons JH, Padidela R, Namba N, Cheong HI, Pitukcheewanont P, Sochett E, Högler W, Muroya K, Tanaka H, Gottesman GS, Biggin A, Perwad F, Mao M, Chen CY, Skrinar A, San Martin J, Portale AA
Lancet 2019 Jun 15;393(10189):2416-2427. Epub 2019 May 16 doi: 10.1016/S0140-6736(19)30654-3. PMID: 31104833Free PMC Article
Clinical exome sequencing: results from 2819 samples reflecting 1000 families.
Trujillano D, Bertoli-Avella AM, Kumar Kandaswamy K, Weiss ME, Köster J, Marais A, Paknia O, Schröder R, Garcia-Aznar JM, Werber M, Brandau O, Calvo Del Castillo M, Baldi C, Wessel K, Kishore S, Nahavandi N, Eyaid W, Al Rifai MT, Al-Rumayyan A, Al-Twaijri W, Alothaim A, Alhashem A, Al-Sannaa N, Al-Balwi M, Alfadhel M, Rolfs A, Abou Jamra R
Eur J Hum Genet 2017 Feb;25(2):176-182. Epub 2016 Nov 16 doi: 10.1038/ejhg.2016.146. PMID: 27848944Free PMC Article

Recent systematic reviews

Whole exome sequencing in fetuses with isolated increased nuchal translucency: a systematic review and meta-analysis.
Di Girolamo R, Rizzo G, Khalil A, Alameddine S, Lisi G, Liberati M, Novelli A, D'Antonio F
J Matern Fetal Neonatal Med 2023 Dec;36(1):2193285. doi: 10.1080/14767058.2023.2193285. PMID: 37019452
Unexplained mismatch repair deficiency: Case closed.
Eikenboom EL, Moen S, van Leeuwen L, Geurts-Giele WRR, Tops CMJ, van Ham TJ, Dinjens WNM, Dubbink HJ, Spaander MCW, Wagner A
HGG Adv 2023 Jan 12;4(1):100167. Epub 2022 Dec 14 doi: 10.1016/j.xhgg.2022.100167. PMID: 36624813Free PMC Article
Expanding the molecular spectrum and the neurological phenotype related to CAMTA1 variants.
Jacobs EZ, Brown K, Byler MC, D'haenens E, Dheedene A, Henderson LB, Humberson JB, van Jaarsveld RH, Kanani F, Lebel RR, Millan F, Oegema R, Oostra A, Parker MJ, Rhodes L, Saenz M, Seaver LH, Si Y, Vanlander A, Vergult S, Callewaert B
Clin Genet 2021 Feb;99(2):259-268. Epub 2020 Nov 23 doi: 10.1111/cge.13874. PMID: 33131045
Is the alpha-galactosidase A variant p.Asp313Tyr (p.D313Y) pathogenic for Fabry disease? A systematic review.
Effraimidis G, Rasmussen ÅK, Bundgaard H, Sørensen SS, Feldt-Rasmussen U
J Inherit Metab Dis 2020 Sep;43(5):922-933. Epub 2020 May 12 doi: 10.1002/jimd.12240. PMID: 32246457
Prevalence of pathogenic variants and variants of unknown significance in patients at high risk of breast cancer: A systematic review and meta-analysis of gene-panel data.
van Marcke C, Collard A, Vikkula M, Duhoux FP
Crit Rev Oncol Hematol 2018 Dec;132:138-144. Epub 2018 Sep 14 doi: 10.1016/j.critrevonc.2018.09.009. PMID: 30447919

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