The Human Gene Mutation Database: 2008 update

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

doi:10.1186/gm13

Cited by 791 publications

(705 citation statements)

References 29 publications

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“…21 The results of our virtual karyotyping support the hypothesis that FH-II is caused by such a mutation. We set two criteria that a polymorphism identified through sequencing had to meet for it to be considered as the causative mutation.…”

Section: Discussionsupporting

confidence: 77%

Further study of chromosome 7p22 to identify the molecular basis of familial hyperaldosteronism type II

et al. 2010

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Familial hyperaldosteronism type II (FH-II) is an inherited form of hyperaldosteronism associated with hypertension in most patients. The mutations that cause FH-II are unknown, but linkage analysis has mapped them to chromosome 7p22. As FH-II is clinically indistinguishable from sporadic primary aldosteronism, a common and treatable condition, unravelling the cause of FH-II has important implications for these sporadic cases. To investigate whether FH-II is caused by large deletions or insertions, we examined the virtual karyotype of four pairs of affected and unaffected individuals using highdensity bead chips. We also sequenced the coding regions of five 7p22 candidate genes that were prioritized because of their putative role in cell growth. We found no evidence of single-nucleotide polymorphism (SNP) copy number variation between pairs, and from the widest gap on the chip, chromosome 7p22 deletions or insertions exceeding B50 kb in these pedigrees can be excluded. We found 15 SNPs (two of which were novel), but none of them were non-synonymous and segregated with the disease in the FH-II pedigrees. We have been able to exclude large genomic deletions or insertions at 7p22 and refine the candidate gene list for this locus, but the mutations causing FH-II remain elusive.

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Section: Discussionsupporting

confidence: 77%

Further study of chromosome 7p22 to identify the molecular basis of familial hyperaldosteronism type II

et al. 2010

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“…gs.washington.edu/SeattleSeqAnnotation137/), and searched in the published literature for pathogenicity and possible functional studies using PubMed and Human Genome Mutation Database public release version (http://www.hgmd.cf.ac.uk/ac/ index.php). 21 Occurrence and frequency was sought in the 1000 Genomes Project data, 22 dbSNP build 137, and the National Heart, Lung and Blood Institute Exome Sequencing Project (ESP) version.0.0.15 (http://evs.gs.washington.edu/EVS/). A minor allele frequency of <1% was used to define a rare variant.…”

Section: Pathogenicity Of Variantsmentioning

confidence: 99%

Determining pathogenicity of genetic variants in hypertrophic cardiomyopathy: importance of periodic reassessment

Ingles

Bagnall

et al. 2014

Genetics in Medicine

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Purpose: Major advances have been made in our understanding and clinical application of genetic testing in hypertrophic cardiomyopathy. Determining pathogenicity of a single-nucleotide variant remains a major clinical challenge. This study sought to reassess single-nucleotide variant classification in hypertrophic cardiomyopathy probands. Methods:Consecutive probands with hypertrophic cardiomyopathy with a reported pathogenic mutation or variation of uncertain significance were included. Family and medical history were obtained. Each single-nucleotide variant was reassessed by a panel of four reviewers for pathogenicity based on established criteria together with updated cosegregation data and current populationbased allele frequencies.Results: From 2000 to 2012, a total of 136 unrelated hypertrophic cardiomyopathy probands had genetic testing, of which 63 (46%) carried at least one pathogenic mutation. MYBPC3 (n = 34; 47%) and MYH7 (n = 23; 32%) gene variants together accounted for 79%. Five variants in six probands (10%) were reclassified: two variation of uncertain significance were upgraded to pathogenic, one variation of uncertain significance and one pathogenic variant were downgraded to benign, and one pathogenic variant (found in two families) was downgraded to variation of uncertain significance. None of the reclassifications had any adverse clinical consequences. Conclusion:Given the rapid growth of genetic information available in both disease and normal populations, periodic reassessment of single-nucleotide variant data is essential in hypertrophic cardiomyopathy.

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“…Fifteen OCA3‐related mutations in the TYRP1 gene have so far been found, including 8 point mutations (C30R, R93C, H215Y, T253M, C290Y, R356Q, M452V, and P513R; Figure S9) 15. Most of these residues contribute to the stability.…”

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confidence: 99%

Structure of Human Tyrosinase Related Protein 1 Reveals a Binuclear Zinc Active Site Important for Melanogenesis

et al. 2017

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Tyrosinase‐related protein 1 (TYRP1) is one of three tyrosinase‐like glycoenzymes in human melanocytes that are key to the production of melanin, the compound responsible for the pigmentation of skin, eye, and hair. Difficulties with producing these enzymes in pure form have hampered the understanding of their activity and the effect of mutations that cause albinism and pigmentation disorders. Herein we show that the typical tyrosinase‐like subdomain of TYRP1 contains two zinc ions in the active site instead of copper ions as found in tyrosinases, which explains why TYRP1 does not exhibit tyrosinase redox activity. In addition, the structures reveal for the first time that the Cys‐rich subdomain, which is unique to vertebrate melanogenic proteins, has an epidermal growth factor‐like fold and is tightly associated with the tyrosinase subdomain. Our structures suggest that most albinism‐related mutations of TYRP1 affect its stability or activity.

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The Human Gene Mutation Database: 2008 update

Cited by 791 publications

References 29 publications

Further study of chromosome 7p22 to identify the molecular basis of familial hyperaldosteronism type II

Further study of chromosome 7p22 to identify the molecular basis of familial hyperaldosteronism type II

Determining pathogenicity of genetic variants in hypertrophic cardiomyopathy: importance of periodic reassessment

Structure of Human Tyrosinase Related Protein 1 Reveals a Binuclear Zinc Active Site Important for Melanogenesis

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