UNC13D R928C - GET-Evidence


UNC13D R928C

(UNC13D Arg928Cys)

Short summary

This variant was seen, along with other variants, in two cases of haemophagocytic lymphohistiocytosis — however, the variant frequency in these cases does not significantly differ from later reported frequency of the variant in exome sequencing data (1.4%). If the variant were causal it would be significantly enriched in cases; instead, it is likely a polymorphism unrelated to the disease in these patients.

Variant evidence
Computational -1

Polyphen 2 predicts probably damaging

Functional -
Case/Control 5

Cases do not significantly differ in frequency from control allele frequency

See Santoro A et al. 2006 (16825436), unpublished research (below).


No familial data

Clinical importance
Severity -
Treatability -
Penetrance -


Low clinical importance, Uncertain benign

(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 ID: rs35037984. Data from exome sequencing project on dbSNP reports this variant has an allele frequency of 1.4% in 3362 sample chromosomes.

Two out of 30 chromosomes in the cases reported by Santoro et al. does not have a statistically significant difference from the 1.4% R928C allele frequency reported in exome sequencing data listed in dbSNP. With this variant frequency, we would expect cases to be significantly enriched for carrying this variant — and so it is highly unlikely that this variant is causal. It is possible R414L or some other unknown cis variant was causal in these cases.

To clarify the significance of the same allele frequencies: If this variant were causing disease, we might attribute it to causing disease in 10% cases caused by UNC13D (which accounts for ~25% of all cases) — with a disease frequency of 1 out of 50,000, this implies an allele frequency of around .002 * .1 * .25 ~= 5 * 10^-5. This differs from the exome sequencing data allele frequency (1.4%) with extremely high statistical significance.

Total cases/controls case+ case– control+ control– p-value odds ratio
Familial Hemophagocytic Lymphohistiocytosis
2 28 0 0 - -


Allele frequency

  • A @ chr17:73826491: 1.6% (169/10732) in EVS
  • Frequency shown in summary reports: 1.6% (169/10732)


Santoro A, Cannella S, Bossi G, Gallo F, Trizzino A, Pende D, Dieli F, Bruno G, Stinchcombe JC, Micalizzi C, De Fusco C, Danesino C, Moretta L, Notarangelo LD, Griffiths GM, Aricò M. Novel Munc13-4 mutations in children and young adult patients with haemophagocytic lymphohistiocytosis. J Med Genet. 2006 Dec;43(12):953-60. Epub 2006 Jul 6. PubMed PMID: 16825436; PubMed Central PMCID: PMC2563207.

In a screen of 15 families with haemophagocytic lymphohistiocytosis, this variant was found in two cases. In both cases, R141L was found along with R928C, presumably indicating these were occurring in cis — which, if either, are causal could not be determined. The cases were both compound heterozygous with another severe mutation (R414L+E616G (splice error) and R414L+R782fsX12).

The authors don’t appear to have examined controls to determine whether these variants occur in the general population.

Cases/controls case+ case– control+ control– p-value odds ratio
Familial Hemophagocytic Lymphohistiocytosis
2 28 - - - -



hu44DCFF - CGI sample GS01669-DNA_C07 from PGP sample 74521372
het A @ chr17:73826491


hu8229AE - CGI sample GS01173-DNA_A07 from PGP sample 96240009
het A @ chr17:73826491


Other external references

  • rs35037984
  • GeneTests records for the UNC13D gene
    Familial Hemophagocytic Lymphohistiocytosis
    Familial Hemophagocytic Lymphohistiocytosis 3
  • Score: 0.998 (probably damaging)

Other in silico analyses

  • NBLOSUM100 score = 8
  • GET-Evidence autoscore = 5

Edit history

Gene search

"GENE" or "GENE A123C":

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