PHYH P29S - GET-Evidence



(PHYH Pro29Ser)

Short summary

Probably benign. This variant was implicated as causing Refsum Disease in a recessive manner, but a subsequent publication noted that all instances were linked with other explanatory mutations. The high allele frequency of this variant in the population (7-13%) contradicts a pathogenic hypothesis.

Variant evidence
Computational 1

Polyphen 2 predicts benign effect.

Functional -
Case/Control 3

Combined data shows equal allele frequency in cases and controls, and the high allele frequency contradicts the originally hypothesized strong pathogenic effect.

Clinical importance


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

The frequency of this variant in 1000 genomes (13.3%) and the high severity of this disease implies that this variant is not a high penetrance allele (which is the hypothesis made by the published research). See also:

The PGP10 genomes and other public Complete Genomics genomes are added below as controls (64 individuals). Once this is added, the variant is found to be no more frequent in cases than it is in controls.

Unpublished cases/controls case+ case– control+ control– p-value odds ratio
Refsum Disease
- - 10 118 - -


Total cases/controls case+ case– control+ control– p-value odds ratio
Refsum Disease
6 65 10 182 0.3838 1.680


Allele frequency

  • A @ chr10:13340236: 15.5% (1671/10758) in EVS
  • A @ chr10:13380241: 7.8% (10/128) in GET-Evidence
  • Frequency shown in summary reports: 15.5% (1671/10758)


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PubMed PMID: 10767344

This fairly common variant in the CEU population was reported in a screen for PHYH variants in patients with autosomal recessive Refsum’s disease: out of 40 patients 2 were reported to be heterozygous for this variant — one carried two other nonsynonymous variants, the other had one other nonsynonymous variant. It was not seen in the additional 38 patients. Controls are not reported, but Jansen et al. 2004 says “[this variant] was not observed when the PHYH cDNA from a group of 64 control individuals was analyzed [Jansen et al., 2000].” Many of the patients appear to be compound heterozygous for various PHYH variants, and so this variant was proposed to be functioning in a recessive compound heterozygous fashion.

Case/control counts the number of carriers of the variant.

Cases/controls case+ case– control+ control– p-value odds ratio
Refsum Disease
2 38 0 64 0.1456


Jansen GA, Waterham HR, Wanders RJ. Molecular basis of Refsum disease: sequence variations in phytanoyl-CoA hydroxylase (PHYH) and the PTS2 receptor (PEX7). Hum Mutat. 2004 Mar;23(3):209-18. Review. PubMed PMID: 14974078.

The authors note that this may be a benign polymorphic variant, since it was always found in combination with additional variant. This article surveys 29 variants in 31 patients. Case/control counts the number of carriers of the variant (one homozygous, three heterozygous).

show discussion


The authors note that: “Patient 2 has c.85C4T and c.658C4T (p.H220Y) on one allele, and c.135-2A>G on the other.” The other three patients have variants that could potentially explain the disease without depending on this variant. In some cases, the phase of the variants is also important. —AWZ

85C>T is the P29S variant. This example states that both this and H220Y were on the same allele, consistent with this allele being found in combination with different possibly explanatory allele. —MPB

Cases/controls case+ case– control+ control– p-value odds ratio
Refsum Disease
4 27 - - - -



hu04FD18 - CGI sample GS00253-DNA_F01_200_37
het A @ chr10:13340236


hu2D6140 - CGI sample GS01173-DNA_F06 from PGP sample 64191565
het A @ chr10:13340236


hu342A08 - CGI sample GS01175-DNA_B05 from PGP sample 83494370
het A @ chr10:13340236



hu4040B8 - CGI sample GS01175-DNA_D01 from PGP sample 31286272
het A @ chr10:13340236


hu4CA5B9 - CGI sample GS01669-DNA_B03 from PGP sample 14427241
het A @ chr10:13340236


hu7A4AD1 - CGI sample GS01669-DNA_C05 from PGP sample 42408046
het A @ chr10:13340236


hu9385BA - CGI sample GS00253-DNA_E01_200_37
hom A @ chr10:13340236


huA0E089 - CGI sample GS01175-DNA_B04 from PGP sample 88590671
het A @ chr10:13340236



huE80E3D - CGI sample GS00253-DNA_D01_200_37
het A @ chr10:13340236


huFAF983 - CGI sample GS01175-DNA_F02 from PGP sample 95788191
het A @ chr10:13340236


GS18501 - var-GS18501-1100-36-ASM
het A @ chr10:13380242




Other external references

  • rs28938169
  • Score: 0.006 (benign)
    Web search results (10 hits -- see all)
  • Mendelian Inheritance in Man Document Reader
    Jansen et al. (2000) determined that the PHYH gene is approximately 21 kb and contains 9 exons and 8 introns. ... in the PHYH gene, leading to a pro29-to-ser (P29S) substitution. ...
  • Refsum's Disease
    We have purified PhyH from rat-liver peroxisomes and determined the N-terminal ... PhyH: the open reading frame encodes a 41.2-kD protein of 338 amino acids, which ...
  • EC - phytanoyl-CoA dioxygenase
    P29S. Homo sapiens. clinically observed mutant is fully active, ... variations in phytanoyl-CoA hydroxylase (PHYH) and the PTS2 receptor (PEX7) ...
  • Dr Brian Gibberd (1931-2006): a pioneering clinician in ...
    The P29S mutant was fully active, implying that the mutation resulted in defective targeting of the protein ... Most point mutations of PhyH causing ARD cluster in two distinct ...
  • Refsum Disease :: enzymology
    BioInfoBank Library :: Refsum Disease :: enzymology :: Further studies on the substrate ... The P29S mutant was fully active, implying that the mutation resulted in defective ...

Other in silico analyses

  • NBLOSUM100 score = 3
  • GET-Evidence autoscore = 4

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Gene search

"GENE" or "GENE A123C":

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