LPL S474X - GET-Evidence

Curation:
Currentness:

LPL S474X

(LPL Ser474Stop)


Short summary

This variant actually increases LPL enzyme activity despite creating a termination codon (see Rip J et al). It appears to be a protective variant, associated with lower triglyceride levels—although the effect is quite weak and explains only 0.5-1% of triglyceride variation.

Variant evidence
Computational 2

Nonsense mutation (2 points)

Functional 1

Gain of function variant.

See Rip J et al. 2006 (16574898).

Case/Control 1

Weak impact seems to imply 1 point (odds ratio very slightly greater than 1). Note that this is actually weakly protective.

See Chasman DI et al. 2008 (19802338).

Familial -
 
Clinical importance
Severity 1

Associated with very low impact on triglycerides level.

Treatability

No standard treatment associated with this variant.

Penetrance -
 

Impact

Low clinical importance, Uncertain protective

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

Inheritance pattern

unknown

Summary of published research, and additional commentary

 

Allele frequency

  • G @ chr8:19819724: 8.4% (909/10758) in EVS
  • G @ chr8:19864003: 6.2% (8/128) in GET-Evidence
  • Frequency shown in summary reports: 8.4% (909/10758)

Publications
 

Rip J, Nierman MC, Ross CJ, Jukema JW, Hayden MR, Kastelein JJ, Stroes ES, Kuivenhoven JA. Lipoprotein lipase S447X: a naturally occurring gain-of-function mutation. Arterioscler Thromb Vasc Biol. 2006 Jun;26(6):1236-45. Epub 2006 Mar 30. Review. PubMed PMID: 16574898.

 

301 Moved Permanently

Moved Permanently

The document has moved here.

PubMed PMID: 17463246

 

Kathiresan S, Melander O, Guiducci C, Surti A, Burtt NP, Rieder MJ, Cooper GM, Roos C, Voight BF, Havulinna AS, Wahlstrand B, Hedner T, Corella D, Tai ES, Ordovas JM, Berglund G, Vartiainen E, Jousilahti P, Hedblad B, Taskinen MR, Newton-Cheh C, Salomaa V, Peltonen L, Groop L, Altshuler DM, Orho-Melander M. Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat Genet. 2008 Feb;40(2):189-97. Epub 2008 Jan 13. Erratum in: Nat Genet. 2008 Nov;40(11):1384. PubMed PMID: 18193044; PubMed Central PMCID: PMC2682493.

 

Chasman DI, Paré G, Zee RY, Parker AN, Cook NR, Buring JE, Kwiatkowski DJ, Rose LM, Smith JD, Williams PT, Rieder MJ, Rotter JI, Nickerson DA, Krauss RM, Miletich JP, Ridker PM. Genetic loci associated with plasma concentration of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, apolipoprotein A1, and Apolipoprotein B among 6382 white women in genome-wide analysis with replication. Circ Cardiovasc Genet. 2008 Oct;1(1):21-30. PubMed PMID: 19802338; PubMed Central PMCID: PMC2630707.

A GWAS study of caucasian women from the Women’s Health Study. The locus associated with this variant was associated with plasma triglycerides with a p-value of 4.7 * 10^-11. The proportion of the residual variance explained by this locus was only 0.50%. This variant was inversely related to triglyceride levels with a beta coefficient of −0.09 (but this explains only 0.5% of triglycerides variation).

Ariza MJ, Sánchez-Chaparro MA, Barón FJ, Hornos AM, Calvo-Bonacho E, Rioja J, Valdivielso P, Gelpi JA, González-Santos P. Additive effects of LPL, APOA5 and APOE variant combinations on triglyceride levels and hypertriglyceridemia: results of the ICARIA genetic sub-study. BMC Med Genet. 2010 Apr 29;11:66. PubMed PMID: 20429872.

This variant is referred to as S447X, indicating we have inconsistency on the amino acid position in the literature. They report a triglyceride levels lowering effect with p < 0.0001. They report the following triglyceride means and 95% confidence intervals: 447SS: 1.15 (1.12-1.19), 447SX: 1.02 (0.96-1.07), 447XX: 0.90 (0.75-1.10). The odds ratio for having hypertriglyceridaemia for carrying this variant alone failed to be significant, although the combined case of this variant and rs320 had weak evidence (p = 0.041).

Franceschini N, Carty C, Buzková P, Reiner A, Garrett T, Lin Y, Vöckler JS, Hindorff LA, Cole SA, Boerwinkle E, Lin DY, Bookman E, Best LG, Bella JN, Eaton C, Greenland P, Jenny N, North KE, Taverna D, Young AM, Deelman E, Kooperberg C, Psaty B, Heiss G. Association of genetic variants and incident coronary heart disease in multi-ethnic cohorts. The PAGE Study. Circ Cardiovasc Genet. 2011 Oct 31. [Epub ahead of print] PubMed PMID: 22042884.

 

Genomes
 

 

 

 

 

 

 

 

 

huC30901 - CGI sample GS00253-DNA_B01_200_37
het G @ chr8:19819724

 

 

GS18558 - var-GS18558-1100-36-ASM
het G @ chr8:19864004

 

GS19020 - var-GS19020-1100-36-ASM
het G @ chr8:19864004

 

GS19648 - var-GS19648-1100-36-ASM
het G @ chr8:19864004

 

GS19649 - var-GS19649-1100-36-ASM
het G @ chr8:19864004

 

GS20502 - var-GS20502-1100-36-ASM
het G @ chr8:19864004

 

Other external references
 

    dbSNP
  • rs328
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    GWAS
  • HDL cholesterol (rs328-G)
    Kathiresan 13-Jan-08 in Nat Genet
    OR or beta: 0.17 [0.13-0.21]% SD higher
    Risk allele frequency: 0.09
    p-value: 9.00E-23
    Initial sample: 2,758 individuals
    Replication sample: 18,544 individuals
    www.ncbi.nlm.nih.gov/pubmed/18193044
  • Triglycerides (rs328-G)
    Kathiresan 13-Jan-08 in Nat Genet
    OR or beta: 0.19 [0.15-0.23]% SD lower
    Risk allele frequency: 0.09
    p-value: 2.00E-28
    Initial sample: 2,758 individuals
    Replication sample: 18,544 individuals
    www.ncbi.nlm.nih.gov/pubmed/18193044
  • Triglycerides (rs328-T)
    Saxena 26-Apr-07 in Science
    OR or beta: 1 % [NR] of variance explained
    Risk allele frequency: 0.10
    p-value: 5.00E-07 (TG)
    Initial sample: up to 5,217 individuals
    Replication sample: NR
    www.ncbi.nlm.nih.gov/pubmed/17463246
    PharmGKB
  • [Cardiovascular Diseases]
    Phenotype: In a GWAS, this SNP was significantly associated with plasma concentrations of triglycerides. Study size:6382. Study population/ethnicity: Caucasian women. Significance metric(s): P = 4.7 x 10(-11). Type of association: CO; GN
    www.ncbi.nlm.nih.gov/pubmed/19802338
    Web search results (8 hits -- see all)
  • Table 1 Text
    ... gene description 1 rs328 LPL 4023 8 19864004 NM_000237 NP_000228 C/G S474X plus 3173350 615 WIAF-CSNP ... rs328 LPL 4023 8 19864004 NM_000237 NP_000228 C/G S474X plus 24648907 ...
    icr.ac.uk/research/research_sections/.../2841.txt
  • Supplementary Table xls.3
    LPL. 4023. 8. 19864004. NM_000237. NP_000228. C/G. S474X. plus. 10467174. 1303 ... LPL. 4023. 8. 19864004. NM_000237. NP_000228. C/G. S474X. plus. 24648907. 1371. PERLEGEN ...
    icr.ac.uk/research/research_sections/.../2845.xls
  • PCPGM: Genotyping
    Footer ... LPL. rs328. S474X. C-->G. MBL2 -221. G-->C. MBL2 -550. G-->C. MBL2. 5UTR +4. C-->A. MBL2. rs1800450. A-->G. MBL2. rs1800451. A-->G. MBL2. rs5030737. A-->G. MC1R. rs ...
    hpcgg.org/Genotyping/SNP_List.jsp?...
  • Blood -- Variants in the ATM-BRCA2-CHEK2 axis predispose to ...
    In addition, 1 SNP encodes a termination codon; S474X in lipoprotein lipase (LPL [MIM 238600]), and a further 31 SNPs are predicted by at least ...
    bloodjournal.hematologylibrary.org/cgi/content/full/108/...
  • Analiza mutacji p.D36N i p.N318S oraz polimorfizmu p.S474X ...
    Ŝ. aj. ą. aktywno. ść. LPL - polimorfizm p.S474X zwi. ę. ksza aktywno. ść. LPL ... sza. aktywno. ść. LPL. poprzez. uwydatnienie funkcji pomostowej prowadz. ą ...
    www.kml.org.pl/downloads/konkurs_prac/prezentacja_12.pdf
  • Human SNPs resulting in premature stop codons and protein ...
    instance, LPL-S474X was located only one amino acid prior. to the natural termination ... IL17RB-Q484X, LPL-S474X, MS4A12-Q71X, OVCH2- W556X, SERPINB11-E90X, ...
    www.ozceliklab.com/papers/H_G_06_01.pdf

Other in silico analyses
 

  • NBLOSUM100 score = 10
  • GET-Evidence autoscore = 5

Edit history
 

Gene search

"GENE" or "GENE A123C":

Log in