Mutation nomenclature extensions and suggestions to describe complex mutations: A discussion

Dunnen, Johan T. den; Antonarakis, Stylianos E.

doi:10.1002/(sici)1098-1004(200001)15:1<7::aid-humu4>3.0.co;2-n

Cited by 1,615 publications

(746 citation statements)

References 4 publications

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“…Differences in nomenclature between ExAC and our internal variant database were reconciled with the HGVS-approved standard for each variant in the data set to ensure accuracy of ascertainment. 6 To derive traceable comparisons for each gene, the evidence supporting phenotype prevalence, locus/allelic heterogeneity, and penetrance was used to estimate the maximal pathogenic allele frequency (MPAF) for each gene (Supplementary Table S1 online). MPAF provides a conservative maximum expected frequency of pathogenic alleles in any gene under the assumption that the corresponding disease is entirely attributable to a single pathogenic variant.…”

Section: Data Collection and Analysismentioning

confidence: 99%

Exploring the landscape of pathogenic genetic variation in the ExAC population database: insights of relevance to variant classification

Song

Gardner

Hovhannisyan

et al. 2016

Genetics in Medicine

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Section: Data Collection and Analysismentioning

confidence: 99%

Exploring the landscape of pathogenic genetic variation in the ExAC population database: insights of relevance to variant classification

Song

Gardner

Hovhannisyan

et al. 2016

Genetics in Medicine

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“…30 When the nucleotide position is indicated, the GenBank cDNA reference sequences were used as follows: AIPL1 (NG_008474.1); CEP290 (NG_008417.1); CRB1 (NG_008483.1); GUCY2D (NG_009092.1); LRAT (NG_009110.1); RDH12 (NG_008321.1); RPE65 (NG_008472.1); RPGRIP1 (NG_008933.1); and TULP1 (NG_009077.1). 31 …”

Section: Sequence Variants Nomenclaturementioning

confidence: 99%

Comprehensive genotyping reveals RPE65 as the most frequently mutated gene in Leber congenital amaurosis in Denmark

et al. 2015

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Leber congenital amaurosis (LCA) represents the most severe form of inherited retinal dystrophies with an onset during the first year of life. Currently, 21 genes are known to be associated with LCA and recurrent mutations have been observed in AIPL1, CEP290, CRB1 and GUCY2D. In addition, sequence analysis of LRAT and RPE65 may be important in view of treatments that are emerging for patients carrying variants in these genes. Screening of the aforementioned variants and genes was performed in 64 Danish LCA probands. Upon the identification of heterozygous variants, Sanger sequencing was performed of the relevant genes to identify the second allele. In combination with prior arrayed primer extension analysis, this led to the identification of two variants in 42 of 86 cases (49%). Remarkably, biallelic RPE65 variants were identified in 16% of the cases, and one novel variant, p.(D110G), was found in seven RPE65 alleles. We also collected all previously published RPE65 variants, identified in 914 alleles of 539 patients with LCA or early-onset retinitis pigmentosa, and deposited them in the RPE65 Leiden Open Variation Database (LOVD). The in silico pathogenicity assessment of the missense and noncanonical splice site variants, as well as an analysis of their frequency in~60 000 control individuals, rendered 864 of the alleles to affect function or probably affect function. This comprehensive database can now be used to select patients eligible for gene augmentation or retinoid supplementation therapies.

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“…The descriptions of the mutations were conformed, if necessary, based on ''Guidelines for mutation nomenclature'' from Human Genome Variation Society. 18 1 V600E in main tumors, and V600_K601delinsE in metastatic lymph nodes (three classic cases). 2 G474R mutant has impaired kinase activity and could be a passenger mutation.…”

Section: A Novel Braf Mutation Detected In Ptcmentioning

confidence: 99%

Functional characterization of the novel BRAF complex mutation, BRAF^V600delinsYM, identified in papillary thyroid carcinoma

Matsuse

Mitsutake

Tanimura

et al. 2012

Intl Journal of Cancer

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An activating mutation in the BRAF gene is the most common genetic alteration in papillary thyroid carcinomas (PTCs). The mutation in PTCs is almost a c.1799T>A transversion, resulting in a p.V600E amino acid substitution (BRAFV600E). Here, we report a novel complex BRAF mutation identified in 4/492 Japanese PTC cases (0.81%). The mutation was comprised of one nucleotide substitution at position 1798, followed by an in‐frame insertion of three nucleotides, c.1798delinsTACA in Exon 15, resulting in p.V600delinsYM. In silico three‐dimensional protein structure prediction implied altered kinase activity of this mutant. In vitro kinase assay and western blotting revealed that this mutation conferred high kinase activity on the BRAF protein, leading to constitutive activation of the MAPK signaling pathway. The mutation also showed high transforming ability in focus formation assay using NIH3T3 cells. The degree of all the functional characteristics was comparable to that of BRAFV600E, and treatment with a BRAF inhibitor Sorafenib was also equally effective in this mutant. These findings suggest that the novel BRAF mutation, BRAFV600delinsYM, is a gain‐of‐function mutation and plays an important role in PTC development.

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Mutation nomenclature extensions and suggestions to describe complex mutations: A discussion

Cited by 1,615 publications

References 4 publications

Exploring the landscape of pathogenic genetic variation in the ExAC population database: insights of relevance to variant classification

Exploring the landscape of pathogenic genetic variation in the ExAC population database: insights of relevance to variant classification

Comprehensive genotyping reveals RPE65 as the most frequently mutated gene in Leber congenital amaurosis in Denmark

Functional characterization of the novel BRAF complex mutation, BRAF^V600delinsYM, identified in papillary thyroid carcinoma

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Mutation nomenclature extensions and suggestions to describe complex mutations: A discussion

Cited by 1,615 publications

References 4 publications

Exploring the landscape of pathogenic genetic variation in the ExAC population database: insights of relevance to variant classification

Exploring the landscape of pathogenic genetic variation in the ExAC population database: insights of relevance to variant classification

Comprehensive genotyping reveals RPE65 as the most frequently mutated gene in Leber congenital amaurosis in Denmark

Functional characterization of the novel BRAF complex mutation, BRAFV600delinsYM, identified in papillary thyroid carcinoma

Contact Info

Product

Resources

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Functional characterization of the novel BRAF complex mutation, BRAF^V600delinsYM, identified in papillary thyroid carcinoma