ENPP1 R774C - GET-Evidence

Curation:
Currentness:

ENPP1 R774C

(ENPP1 Arg774Cys)


Short summary

Tentatively classified as benign. Initially reported as a recessive cause of infantile arterial calcification, but with no statistical significance. Other variants have been implicated as causal in these cases this variant. 5% allele frequency in caucasians contradicts this variant as having any highly pathogenic effect.

Variant evidence
Computational -
Functional -
Case/Control 1

No statistically significant data supports a pathogenic effect, and 5% allele frequency contradicts a highly penetrant effect.

Familial

No significant familial data.

 
Clinical importance
Severity
Treatability
Penetrance
 

Impact

Low clinical importance, Uncertain benign

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

Inheritance pattern

undefined

Summary of published research, and additional commentary

dbSNP reports that this variant has 5% allele frequency in a low-coverage CEU panel (6/120 chromosomes, from 1000 genomes) and 2.6% in a mixed panel of Caucasian & African American samples (2/78 chromosomes). Lorenz-Depiereux et al. point to this as suggesting that the variant is a not causal.

http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=28933977

The predicted incidence of homozygotes (1 in 400) vs. the incidence of the disease (quite rare) implies that this variant cannot have a high penetrance pathogenic effect. There is no statistically significant higher incidence of this variant in Rutsch et al’s findings when compared to combined dbSNP numbers. In addition, all reported cases with this variant now have other causal variants implicated. For this reason, we mark the variant as benign.

Allele frequency

  • T @ chr6:132206079: 2.6% (278/10758) in EVS
  • Frequency shown in summary reports: 2.6% (278/10758)

Publications
 

Rutsch F, Ruf N, Vaingankar S, Toliat MR, Suk A, Höhne W, Schauer G, Lehmann M, Roscioli T, Schnabel D, Epplen JT, Knisely A, Superti-Furga A, McGill J, Filippone M, Sinaiko AR, Vallance H, Hinrichs B, Smith W, Ferre M, Terkeltaub R, Nürnberg P. Mutations in ENPP1 are associated with 'idiopathic' infantile arterial calcification. Nat Genet. 2003 Aug;34(4):379-81. PubMed PMID: 12881724.

In a study of 11 idiopathic cases of infantile arterial calcification, this variant was reported homozygously in one case and heterozygously in combination with L579F (in cis) and a frameshift (in trans) in another. Counting alleles, this is a case+: 3, case-: 19. If we use the combined data from dbSNP, control+: 8, control-: 190. This has p=0.08.

Lorenz-Depiereux B, Schnabel D, Tiosano D, Häusler G, Strom TM. Loss-of-function ENPP1 mutations cause both generalized arterial calcification of infancy and autosomal-recessive hypophosphatemic rickets. Am J Hum Genet. 2010 Feb 12;86(2):267-72. Epub 2010 Feb 4. PubMed PMID: 20137773; PubMed Central PMCID: PMC2820166.

The footnote to Table 3 states: “The mutation reported in this paper (c.2320C>T [p.Arg774Cys]) has since been shown to be a polymorphism (rs28933977) with a minor allele frequency of 5%.”

These authors follow up on the homozygous case from Rutsch et al, a Turkish family, and find the patient is also homozygous for E266V. The father is homozygous for the E266V variant as well but has a later onset phenotype, developing an aortic root dissection at the age of 28 yrs.

Genomes
 

Other external references
 

    dbSNP
  • rs28933977
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    PolyPhen-2
  • Score: 0.746 (possibly damaging)

Other in silico analyses
 

  • NBLOSUM100 score = 8
  • GET-Evidence autoscore = 3

Edit history
 

Gene search

"GENE" or "GENE A123C":

Log in