PHYKPL

protein-coding

5-phosphohydroxy-L-lysine phospho-lyase

Gene summary

This is a nuclear gene encoding a mitochondrial enzyme that catalyzes the conversion of 5-phosphonooxy-L-lysine to ammonia, inorganic phosphate, and 2-aminoadipate semialdehyde. Mutations in this gene may cause phosphohydroxylysinuria. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2013]

Previous symbols:

AGXT2L2

MANE transcript

NM_153373.4

Inheritance

ClinVar variants

U:99B:16

Top phenotype

Phosphohydroxylysinuria

gnomAD constraint

pLI —, LoF o/e 0.96

Max pathogenic AF

—

Genomic locus

chr5:178,208,471-178,232,802

External References & Databases

Ensembl (ENSG00000175309)

Transcript & Mutation Effects

hg38 • Region Span ~24.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

phosphohydroxylysinuriaLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014008

Submitter: PanelApp Australia

phosphohydroxylysinuriaLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014008

Submitter: ClinGen

PHYKPL was first reported in relation to autosomal recessive phosphohydroxylysinuria in 2013 (Veiga-da-Cunha M, et al., 2013, PMID: 23242558). The disease was first described by Dorland et al., 1990 (PMID: 2387074) from two patients with neurological problems, however these symptoms could be attributed to infectious causes in both cases. The two original cases were not available for molecular analysis of PHYKPL. A third case was subsequently identified and two unique missense variants were reported in this single case (PMID: 23242558). This case was not reported to have neurological problems but did have an Ehler-Danlos phenotype, thought to be unrelated to her metabolic defect. From the limited information available at this time it is difficult to determine if phosphohydroxylysinuria is a neurometabolic disease or an isolated metabolic abnormality. In addition to the single case, evidence supporting this gene-disease relationship includes the experimental data establishing the role of PHYKPL in the breakdown of 5-phosphohydroxy-L-lysine (PMID: 22241472) and a knockout mouse model from the International Mouse Phenotyping Consortium with limited relevant characterization. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This gene-disease pair was previously approved by the Aminoacidopathy GCEP on 09/25/2020. It was reevaluated on 10/25/2023. As a result of this reevaluation, the classification remained Limited with no new evidence identified.

Clinical Genomic Database (CGD)

PhosphohydroxylysinuriaAR

Manifestation: Biochemical

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: Individuals have been described with multiple phenotypes, but the overall consequences are unclear

Refs: 2387074; 23242558

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PHYKPL variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 119

PHYKPL-related disorderTotal: 6

PhosphohydroxylysinuriaTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_153373.4. 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			2 clinvar	4 clinvar		6
missense			96 clinvar	10 clinvar	2 clinvar	108
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	0	99	14	2	115

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 133 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_153373.4	RefSeq	NP_699204.1	12	MANE Select
ENST00000308158.10	Ensembl	ENSP00000310978.5	12	MANE Select
NM_001278346.1	RefSeq	NP_001265275.1	11	Standard
ENST00000323594.10	Ensembl	ENSP00000321290.5	12	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Lysine degradation - Homo sapiens (human)
Lysine catabolism
Collagen degradation
Histidine, lysine, phenylalanine, tyrosine, proline and tryptophan catabolism
Metabolism of amino acids and derivatives

Biological Process

lysine catabolic process
collagen catabolic process

Molecular Function

protein binding
transaminase activity
lyase activity
pyridoxal phosphate binding
identical protein binding

Cellular Component

mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000308158
Coding exons: 12
Length: 24295
Individuals with no LoFs: 125602
Homozygous LoFs: 0
Heterozygous LoFs: 146
Defined: 125748
p: 0.000581

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.476	295	273	1.08	0.0000163	2938
Missense (PolyPhen)		104	100.39	1.036		1020
Synonymous	-0.657	124	115	1.08	0.00000759	886
Loss of Function	0.170	21	21.9	0.961	9.29e-7	259

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00037	0.00037	rare
Latino/Admixed American	0.00023	0.00023	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00093	0.00092	rare
Finnish	0.00075	0.00074	rare
European (Non-Finnish)	0.00063	0.00062	rare
South Asian	0.00072	0.00072	rare
Other	0.00084	0.00081	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the pyridoxal-phosphate-dependent breakdown of 5-phosphohydroxy-L-lysine, converting it to ammonia, inorganic phosphate and 2-aminoadipate semialdehyde. {ECO:0000269|PubMed:22241472}.;
Disease: DISEASE: Phosphohydroxylysinuria (PHLU) [MIM:615011]: A condition characterized by elevated phosphohydroxylysine in the urine. There is no clinical phenotype associated with this finding other than the urinary metabolites. {ECO:0000269|PubMed:23242558}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.122

Intolerance Scores

RVIS EVS: 0.09
RVIS percentile EVS: 60.57

Essentials

Essential (CRISPR): N
Essential (gene trap): N

Gene Damage Prediction

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