ENPP1 R774C - GET-Evidence


(See the latest version)


(ENPP1 Arg774Cys)

You are viewing an old version of this page that was saved on May 2, 2011 at 6:33pm by Madeleine Ball.

Edited in this revision:

Short summary

Initially reported as a recessive cause of infantile arterial calcification, but the finding had no statistical significance. Later, the allele frequency has been reported as 5% in caucasians. This contradicts the variant as having a highly penetrant pathogenic effect, but does not prove it is non-pathogenic; Lorentz et al. call it a variant of unknown significance.

Variant evidence
Computational -
Functional -
Case/Control -1

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

See Lorenz-Depiereux B et al. 2010 (20137773).


No significant familial data.

Clinical importance
Severity 4

Potentially lethal, variable onsets reported.

See Lorenz-Depiereux B et al. 2010 (20137773).

Treatability 3
Penetrance 2

Initial report suggested highly penetrant effect, but this is contradicted by a relatively high 5% allele frequency.



Low clinical importance, Uncertain pathogenic

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

Inheritance pattern


Summary of published research, and additional commentary

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


The predicted incidence of homozygotes (1 in 400) vs. the incidence of the disease (quite rare) implies that this variant is a highly penetrant causal variant. It may have a modifier or susceptibility effect though (note that the son of the reported family in Lorenz-Depiereux et al. & Rutsch et al. had a more severe effect compared to his father).

Allele frequency

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


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. This is a case+: 3, case-: 19.

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.


Other external references

  • 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