NPC1 H215R - GET-Evidence

Curation:
Currentness:

NPC1 H215R

(NPC1 His215Arg)


Short summary

This variant is associated with a reduced risk of obesity, with an additive effect of -0.084 BMI per allele (an average of 0.54 pounds less, per allele, in a 5’6” individual).

Variant evidence
Computational 2

Gene is associated with weight differences in mice
PolyPhen: Benign 0.000
SIFT: TOLERATED 0.51
GVGD: GV 98.69; GD 14.11; Class C0
Variant Effect Predictor (Ensembl ):
SIFT=tolerated(0.5);
PolyPhen=benign(0);
Condel=deleterious(0.513)

See Jelinek D et al. 2010 (19910939).

Functional -
Case/Control 4

High significance in replicate follow-up confirming GWAS finding (p = 0.0024)

See Meyre D et al. 2009 (19151714).

Familial -
 
Clinical importance
Severity 3
Treatability -
Penetrance 2

~2% attributable decreased risk, see Meyre et al. analysis below

See Meyre D et al. 2009 (19151714).

 

Impact

Low clinical importance, Likely protective

(The "low clinical importance, likely" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern

other

Summary of published research, and additional commentary

 

Allele frequency

  • C @ chr18:21140432: 29.6% (3181/10758) in EVS
  • C @ chr18:19394429: 25.0% (32/128) in GET-Evidence
  • Frequency shown in summary reports: 29.6% (3181/10758)

Publications
 

Meyre D, Delplanque J, Chèvre JC, Lecoeur C, Lobbens S, Gallina S, Durand E, Vatin V, Degraeve F, Proença C, Gaget S, Körner A, Kovacs P, Kiess W, Tichet J, Marre M, Hartikainen AL, Horber F, Potoczna N, Hercberg S, Levy-Marchal C, Pattou F, Heude B, Tauber M, McCarthy MI, Blakemore AI, Montpetit A, Polychronakos C, Weill J, Coin LJ, Asher J, Elliott P, Järvelin MR, Visvikis-Siest S, Balkau B, Sladek R, Balding D, Walley A, Dina C, Froguel P. Genome-wide association study for early-onset and morbid adult obesity identifies three new risk loci in European populations. Nat Genet. 2009 Feb;41(2):157-9. Epub 2009 Jan 18. PubMed PMID: 19151714.

This variant was associated with being protective vs. obesity, with a p-value in the initial association for obesity in adults of 2.6 * 10^-6 under an additive model. In a replicate follow-up this had a p-value of 2.4 times 10-3. The odds ratio in the replicate adults was 0.71, and 0.75 in obese children. They associate this with a per-allele average BMI difference of -0.087. In a 5’ 6” individual this corresponds to 0.54 less pounds on average per allele.

To estimate attributable decreased risk, we use data from Swiss adults in supplementary table 3, as the controls represent a random selection rather than lean individuals. Obese adult cases have an allele frequency of 0.308, while random adults had an allele frequency of 0.411. Assuming an incidence of obesity of 10%, this corresponds to an attributable decreased risk of 2.3%.

Hofker M, Wijmenga C. A supersized list of obesity genes. Nat Genet. 2009 Feb;41(2):139-40. PubMed PMID: 19174833.

Review article of obesity GWAS studies, including Meyre et al.

Jelinek D, Heidenreich RA, Erickson RP, Garver WS. Decreased Npc1 gene dosage in mice is associated with weight gain. Obesity (Silver Spring). 2010 Jul;18(7):1457-9. Epub 2009 Nov 12. PubMed PMID: 19910939.

 

Genomes
 

hu011C57 - CGI sample GS01669-DNA_B05 from PGP sample 86486261
het C @ chr18:21140432

 

hu034DB1 - CGI sample GS00253-DNA_A02_200_37
het C @ chr18:21140432

 

hu0D879F - CGI sample GS00253-DNA_G01_200_37
het C @ chr18:21140432

 

hu0E64A1 - CGI sample GS01173-DNA_B02 from PGP sample 94378523
hom C @ chr18:21140432

 

 

hu2D6140 - CGI sample GS01173-DNA_F06 from PGP sample 64191565
hom C @ chr18:21140432

 

hu2DBF2D - CGI sample GS01173-DNA_G02 from PGP sample 67180598
het C @ chr18:21140432

 

hu38168C - CGI sample GS01173-DNA_H06 from PGP sample 91708424
het C @ chr18:21140432

 

 

hu3CAB43 - CGI sample GS01175-DNA_D03 from PGP sample 27486199
het C @ chr18:21140432

 

hu4040B8 - CGI sample GS01175-DNA_D01 from PGP sample 31286272
het C @ chr18:21140432

 

hu4339C0 - CGI sample GS01175-DNA_H01 from PGP sample 94797469
hom C @ chr18:21140432

 

 

hu7A4AD1 - CGI sample GS01669-DNA_C05 from PGP sample 42408046
hom C @ chr18:21140432

 

hu8229AE - CGI sample GS01173-DNA_A07 from PGP sample 96240009
het C @ chr18:21140432

 

hu92C40A - CGI sample GS01175-DNA_G03 from PGP sample 92527586
het C @ chr18:21140432

 

hu9385BA - CGI sample GS00253-DNA_E01_200_37
het C @ chr18:21140432

 

 

huAE6220 - CGI sample GS00253-DNA_H01_200_37
hom C @ chr18:21140432

 

huB1FD55 - CGI sample GS01173-DNA_B07 from PGP sample 61499538
hom C @ chr18:21140432

 

huBAAC98 - CGI sample GS01173-DNA_F02 from PGP sample 70008981
hom C @ chr18:21140432

 

huBEDA0B - CGI sample GS00253-DNA_C01_200_37
hom C @ chr18:21140432

 

huC30901 - CGI sample GS00253-DNA_B01_200_37
het C @ chr18:21140432

 

huD81F3D - CGI sample GS01173-DNA_D06 from PGP sample 69488604
het C @ chr18:21140432

 

huFFAD87 - CGI sample GS01669-DNA_H05 from PGP sample 10971581
het C @ chr18:21140432

 

GS06985 - var-GS06985-1100-36-ASM
het C @ chr18:19394430

 

GS07357 - var-GS07357-1100-36-ASM
het C @ chr18:19394430

 

GS10851 - var-GS10851-1100-36-ASM
hom C @ chr18:19394430

 

GS18555 - var-GS18555-1100-36-ASM
het C @ chr18:19394430

 

GS18947 - var-GS18947-1100-36-ASM
het C @ chr18:19394430

 

GS19648 - var-GS19648-1100-36-ASM
het C @ chr18:19394430

 

GS19649 - var-GS19649-1100-36-ASM
het C @ chr18:19394430

 

GS19669 - var-GS19669-1100-36-ASM
het C @ chr18:19394430

 

GS19670 - var-GS19670-1100-36-ASM
het C @ chr18:19394430

 

GS19701 - var-GS19701-1100-36-ASM
het C @ chr18:19394430

 

GS20509 - var-GS20509-1100-36-ASM
het C @ chr18:19394430

 

Other external references
 

    dbSNP
  • rs1805081
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    GWAS
  • Obesity (rs1805081-A)
    Meyre 18-Jan-09 in Nat Genet
    OR or beta: 1.33 [1.08-1.75]
    Risk allele frequency: 0.56
    p-value: 3.00E-07 (children)
    Initial sample: 695 obese adults, 685 obese children, 731 lean adults, 685 lean children
    Replication sample: 1,171 obese adults, 896 obese children, 1,114 lean adults, 1,297 lean children, 4,417 adults, 5,291 children
    www.ncbi.nlm.nih.gov/pubmed/19151714
    PharmGKB
  • [Obesity]
    GWAS results: Genome-wide association study for early-onset and morbid adult obesity identifies three new risk loci in European populations. (Initial Sample Size: 695 obese adults, 685 obese children, 731 lean adults, 685 lean children; Replication Sample Size: 1,171 obese adults, 896 obese children, 1,114 lean adults, 1,297 lean children, 4,417 adults, 5,291 children); (Region: 18q11.2; Reported Gene(s): NPC1; Risk Allele: rs1805081-A); (p-value= 0.0000003).This variant is associated with Obesity.
    www.ncbi.nlm.nih.gov/pubmed/19151714; Web Resource:http://www.genome.gov/gwastudie
  • [Obesity]
    The analyses of genome-wide association data from 1,380 Europeans with early-onset and morbid adult obesity and 1,416 age-matched normal-weight controls found an association of this variant (rs1805081) in NPC1 for risk of pooled childhood and adult severe obesity.
    www.ncbi.nlm.nih.gov/pubmed/19174833
    PolyPhen-2
  • Score: 0 (benign)
    Web search results (52 hits -- see all)
  • NPC-db: Niemann-Pick Type C Disease Gene Variation Database
    Variation name : p.H215R. Gene Name : NPC1. Position in Gene : Exon 6 ... cis: p.Y129Y (het), p.H215R (het), p.I642M (het), p.D948N (het), p.I858V (het) ...
    npc.fzk.de/index.php?section=view_detail&Mutation_ID=15
  • Obesity [PharmGKB]
    rs1805081 at chr18:19394430 in NPC1. The analyses of genome-wide ... variant (rs1805081) in NPC1 for risk of pooled childhood and adult severe obesity. Variant Name: NPC1: H215R ...
    pharmgkb.org/views/index.jsp?objCls=Disease&objId=PA445131
  • NPC-db: Niemann-Pick Type C Disease Gene Variation Database
    NPC1. Position in Gene : Exon 4. DNA : c.387T>C. Protein : p.Y129Y. Protein Domain : ... cis: p.Y129Y (het), p.H215R (het), p.I642M (het), p.D948N (het), p.I858V (het) ...
    npc.fzk.de/index.php?section=view_detail&Mutation_ID=7
  • Niemann-Pick type C disease: mutations of NPC1 gene and ...
    mutations of NPC1 gene and evidence of abnormal expression of some mutant alleles in ... controls: T387C (Y129Y), A644G (H215R), C1926G (I642M), A2572G (I858V) ...
    www.jlr.org/cgi/content/full/43/11/1908
  • 1 NIEMANN-PICK TYPE C DISEASE. MUTATIONS OF NPC1 GENE AND ...
    We analysed NPC1 gene in 12 patients with Niemann-Pick type C disease by sequencing both ... both NPC1 patients and controls: T387C (Y129Y), A644G (H215R), C1926G ...
    www.jlr.org/cgi/reprint/M200203-JLR200v1.pdf
  • Niemann-Pick C1 Disease: The I1061T Substitution Is a ...
    Our initial study of 25 patients with NPC1 identified a T3182C transition that leads to ... data) disclosed a very large mutational spectrum in patients with NPC1. ...
    www.ncbi.nlm.nih.gov/pmc/articles/PMC1288284
  • Niemann-Pick C1 Disease: The I1061T Substitution Is a ...
    A genetic heterogeneity (NPC1 and NPC2) was estab- lished by cell-hybridization and ... with NPC1. In the process of a complete mutational analysis in. 25 NPC1 patients covering ...
    sciencedirect.com/science?_ob=MImg&...&ie=/sdarticle.pdf
  • NPC1 [PharmGKB]
    rs1805081 at chr18:19394430 in NPC1. The analyses of genome-wide ... NPC1: H215R. Related Diseases: Obesity. Evidence: PMID:19174833. Non-Curated Annotations ...
    www.pharmgkb.org/do/serve?objId=PA31698&objCls=Gene
  • GM18390
    NPC1 GENE; NPC1. IDENTIFICATION OF SPECIES OF ORIGIN. Species of Origin ... is a compound heterozygote at the NPC1 gene locus: allele 1 carries a ...
    ccr.coriell.org/Sections/Search/...?Ref=GM18390&PgId=166
  • GM18388
    NPC1 GENE; NPC1. Passage Frozen. 9. IDENTIFICATION OF SPECIES OF ORIGIN ... 607623 NPC1 GENE; NPC1. Omim Description. NIEMANN-PICK DISEASE WITH CHOLESTEROL ...
    ccr.coriell.org/Sections/Search/...?Ref=GM18388&PgId=166

Other in silico analyses
 

  • NBLOSUM100 score = 1
  • GET-Evidence autoscore = 4

Edit history
 

Gene search

"GENE" or "GENE A123C":

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