The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine

Stenson, Peter D.; Mort, Matthew; Ball, Edward V.; Shaw, Katy; Phillips, Andrew David; Cooper, David Neil

doi:10.1007/s00439-013-1358-4

Cited by 1,181 publications

(1,108 citation statements)

References 46 publications

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“…Variant information was gathered from population databases (Exome Aggregation Consortium 14 , Exome Variant server 15 , 1000 Genomes 16 , dbSNP 17 and dbVAR 18 ), disease databases (humsavar.txt release 2016_05 19 , ClinVar 20 , HGMD-public 21 , OMIM 22 and OMIA 23 ) and sequence databases (RefSeqGene 24 , NCBI Genome 25 , UCSC Genome 26 and Ensembl Genome 27 ). I-Mutant2.0 28 was used as a predictor of protein stability changes upon variations.…”

Section: Bioinformatics Tools For Sequence Variant Interpretationmentioning

confidence: 99%

The novel homozygous KCNJ10 c.986T>C (p.(Leu329Pro)) variant is pathogenic for the SeSAME/EAST homologue in Malinois dogs

et al. 2016

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SeSAME/EAST syndrome is a multisystemic disorder in humans, characterised by seizures, sensorineural deafness, ataxia, developmental delay and electrolyte imbalance. It is exclusively caused by homozygous or compound heterozygous variations in the KCNJ10 gene. Here we describe a similar syndrome in two families belonging to the Malinois dog breed, based on clinical, neurological, electrodiagnostic and histopathological examination. Genetic analysis detected a novel pathogenic KCNJ10 c.986T4C (p.(Leu329Pro)) variant that is inherited in an autosomal recessive way. This variant has an allele frequency of 2.9% in the Belgian Malinois population, but is not found in closely related dog breeds or in dog breeds where similar symptoms have been already described. The canine phenotype is remarkably similar to humans, including ataxia and seizures. In addition, in half of the dogs clinical and electrophysiological signs of neuromyotonia were observed. Because there is currently no cure and treatment is nonspecific and unsatisfactory, this canine translational model could be used for further elucidating the genotype/ phenotype correlation of this monogenic multisystem disorder and as an excellent intermediate step for drug safety testing and efficacy evaluations before initiating human studies.

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Section: Bioinformatics Tools For Sequence Variant Interpretationmentioning

confidence: 99%

The novel homozygous KCNJ10 c.986T>C (p.(Leu329Pro)) variant is pathogenic for the SeSAME/EAST homologue in Malinois dogs

et al. 2016

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“…20 This set of disease-causing variants is representative of data sets that have typically been employed in the training and evaluation of a number of different bioinformatic prediction tools to identify disease-causing AAS. In order to allow an unbiased evaluation of bioinformatic prediction tools, an unseen test set (not used for training) should always be used, otherwise the evaluation represents in-sample error rather than out-of-sample error and hence is likely to be overly optimistic in terms of prediction performance.…”

Section: Dm Setmentioning

confidence: 99%

Improving the in silico assessment of pathogenicity for compensated variants

et al. 2016

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Understanding the functional sequelae of amino-acid replacements is of fundamental importance in medical genetics. Perhaps, the most intuitive way to assess the potential pathogenicity of a given human missense variant is by measuring the degree of evolutionary conservation of the substituted amino-acid residue, a feature that generally serves as a good proxy metric for the functional/ structural importance of that residue. However, the presence of putatively compensated variants as the wild-type alleles in orthologous proteins of other mammalian species not only challenges this classical view of amino-acid essentiality but also precludes the accurate evaluation of the functional impact of this type of missense variant using currently available bioinformatic prediction tools. Compensated variants constitute at least 4% of all known missense variants causing human-inherited disease and hence represent an important potential source of error in that they are likely to be disproportionately misclassified as benign variants. The consequent under-reporting of compensated variants is exacerbated in the context of next-generation sequencing where their inappropriate exclusion constitutes an unfortunate natural consequence of the filtering and prioritization of the very large number of variants generated. Here we demonstrate the reduced performance of currently available pathogenicity prediction tools when applied to compensated variants and propose an alternative machine-learning approach to assess likely pathogenicity for this particular type of variant.

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“…In addition to the primary phenotypic categorization, all other symptoms were noted by selecting any applicable lowerlevel Human Phenotype Ontology terms and Human Gene Mutation Database (HGMD) disease terms. 12,13 Genomic DNA was extracted from whole blood obtained from the affected individual and any submitted family members. Clinicians were encouraged to provide blood or DNA specimens for both parents and all available affected family members whenever possible.…”

Section: Introductionmentioning

confidence: 99%

Clinical application of whole-exome sequencing across clinical indications

Retterer¹,

Juusola²,

Cho³

et al. 2016

Genetics in Medicine

825

716

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Purpose:We report the diagnostic yield of whole-exome sequencing (WES) in 3,040 consecutive cases at a single clinical laboratory.Methods: WES was performed for many different clinical indications and included the proband plus two or more family members in 76% of cases. Results:The overall diagnostic yield of WES was 28.8%. The diagnostic yield was 23.6% in proband-only cases and 31.0% when three family members were analyzed. The highest yield was for patients who had disorders involving hearing (55%, N = 11), vision (47%, N = 60), the skeletal muscle system (40%, N = 43), the skeletal system (39%, N = 54), multiple congenital anomalies (36%, N = 729), skin (32%, N = 31), the central nervous system (31%, N = 1,082), and the cardiovascular system (28%, N = 54). Of 2,091 cases in which secondary findings were analyzed for 56

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The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine

Cited by 1,181 publications

References 46 publications

The novel homozygous KCNJ10 c.986T>C (p.(Leu329Pro)) variant is pathogenic for the SeSAME/EAST homologue in Malinois dogs

The novel homozygous KCNJ10 c.986T>C (p.(Leu329Pro)) variant is pathogenic for the SeSAME/EAST homologue in Malinois dogs

Improving the in silico assessment of pathogenicity for compensated variants

Clinical application of whole-exome sequencing across clinical indications

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