PHYH

protein-coding

phytanoyl-CoA 2-hydroxylase

Gene summary

This gene is a member of the PhyH family and encodes a peroxisomal protein that is involved in the alpha-oxidation of 3-methyl branched fatty acids. Specifically, this protein converts phytanoyl-CoA to 2-hydroxyphytanoyl-CoA. Mutations in this gene have been associated with Refsum disease (RD) and deficient protein activity has been associated with Zellweger syndrome and rhizomelic chondrodysplasia punctata. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

MANE transcript

NM_006214.4

Inheritance

ClinVar variants

P:110U:178B:129

Top phenotype

Refsum disease

gnomAD constraint

pLI —, LoF o/e 0.68

Max pathogenic AF

—

Genomic locus

chr10:13,277,796-13,302,412

External References & Databases

Ensembl (ENSG00000107537)

Transcript & Mutation Effects

hg38 • Region Span ~24.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

adult Refsum diseaseSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009958

Submitter: PanelApp Australia

adult Refsum diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009958

Submitter: G2P

adult Refsum diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009958

Submitter: Ambry Genetics

phytanoyl-CoA hydroxylase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100258

Submitter: ClinGen

*PHYH* was first reported in relation to autosomal recessive phytanoyl-CoA hydroxylase deficiency (adult Refsum disease included) in 1997 (Jansen et al., PMID: 9326940). Numerous variants have been reported in humans per ClinVar. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of case-level and experimental data: 14.5 points. Variants in this gene have been reported in at least 16 probands in 4 publications (PMIDS: 25604618, 31240149, 17905308,10767344, 9326940, 22156782, 9326939, 28681609). This gene-disease association is supported by animal models and in vitro functional assays. In summary, *PHYH* is definitively associated with autosomal recessive phytanoyl-CoA hydroxylase deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.

adult Refsum diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009958

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

adult Refsum diseaseSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009958

Submitter: Labcorp Genetics (formerly Invitae)

adult Refsum diseaseSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009958

Submitter: Orphanet

Clinical Genomic Database (CGD)

Refsum diseaseAR

Manifestation: Audiologic/Otolaryngologic; Biochemical; Cardiovascular; Dermatologic; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: Biochemical; Cardiovascular; Pharmacogenomic

Rationale: Dietary measures (high calorie diet with phytanic acid restriction) may be beneficial; Surveillance can allow early diagnosis and treatment of cardiac manifestsations (eg, cardiac arrhythmias, cardiomyopathy); Plasmapheresis/lipid apheresis may be indicated in severe situations; Certain agents/circumstances (eg, fasting, ibuprofen) should be avoided

Refs: 13045168; 18140089; 4159604; 85164; 6160883; 2452736; 9326939; 9326940; 10767344; 17905308; 20301527; 20547622; 22156782

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PHYH variants in ClinVar

15 Conditions Cataloged

not providedTotal: 437

Refsum disease, classicTotal: 110

not specifiedTotal: 58

Inborn genetic diseasesTotal: 50

PHYH-related disorderTotal: 47

REFSUM DISEASE, ADULT, 1Total: 8

Retinal dystrophyTotal: 8

Retinitis pigmentosaTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006214.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			6 clinvar	117 clinvar		123
missense	3 clinvar	9 clinvar	166 clinvar	11 clinvar	1 clinvar	190
nonsense	11 clinvar	11 clinvar	2 clinvar			24
start loss		3 clinvar	1 clinvar			4
frameshift	33 clinvar	19 clinvar				52
splice donor/acceptor (+/-2bp)	1 clinvar	20 clinvar	3 clinvar			24
Total	48	62	178	128	1	417

Highest pathogenic variant AF is 0.00016865932

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 63 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006214.4	RefSeq	NP_006205.1	9	MANE Select
ENST00000263038.9	Ensembl	ENSP00000263038.4	9	MANE Select
NM_001037537.2	RefSeq	NP_001032626.1	6	Standard
NM_001323080.2	RefSeq	NP_001310009.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Peroxisome - Homo sapiens (human)
Oxidation of Branched Chain Fatty Acids
Refsum Disease
Phytanic Acid Peroxisomal Oxidation
Metabolism of lipids

Biological Process

fatty acid alpha-oxidation
2-oxoglutarate metabolic process
protein targeting to peroxisome
isoprenoid metabolic process
methyl-branched fatty acid metabolic process

Molecular Function

protein binding
ferrous iron binding
carboxylic acid binding
L-ascorbic acid binding
cofactor binding

Cellular Component

peroxisome
peroxisomal matrix
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000263038
Coding exons: 9
Length: 24617
Individuals with no LoFs: 125689
Homozygous LoFs: 0
Heterozygous LoFs: 59
Defined: 125748
p: 0.000235

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0310	194	195	0.994	0.0000113	2245
Missense (PolyPhen)		53	53.778	0.98554		597
Synonymous	0.292	72	75.2	0.957	0.00000522	619
Loss of Function	1.20	11	16.2	0.678	6.96e-7	200

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.00017	0.00017	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0.00046	0.00046	rare
European (Non-Finnish)	0.00032	0.00032	rare
South Asian	0.000033	0.000033	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Converts phytanoyl-CoA to 2-hydroxyphytanoyl-CoA.;

Recessive Scores

pRec: 0.229

Intolerance Scores

LoFtool: 0.119
RVIS EVS: 0.62
RVIS percentile EVS: 83.36

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.670

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium