PCYT1A
protein-codingphosphate cytidylyltransferase 1A, choline
Gene summary
This gene belongs to the cytidylyltransferase family and is involved in the regulation of phosphatidylcholine biosynthesis. Mutations in this gene are associated with spondylometaphyseal dysplasia with cone-rod dystrophy. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2015]
- PCYT1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~73.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0012160
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0012160
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0012160
Submitter: ClinGen
PCYT1A was first reported in relation to autosomal recessive spondylometaphyseal dysplasia with cone-rod dystrophy in 2014 (Hoover-Fong et al., PMID: 24387990; Yamamoto et al., PMID: 24387991 ). Spondylometaphyseal dysplasia with cone-rod dystrophy (SMDCRD) is characterized by postnatal growth deficiency resulting in profound short stature, rhizomelia with bowing of the lower extremities, platyspondyly with anterior vertebral protrusions, progressive metaphyseal irregularity and cupping with shortened tubular bones, and early-onset progressive visual impairment associated with a pigmentary maculopathy and electroretinographic evidence of cone-rod dysfunction. Later, Testa et al reported biallelic PCYT1A variants in three young patients from two different Italian families with isolated retinal dystrophy (PMID: 28272537). At least 11 variants (variant types including missense, nonsense and frameshift) that have been reported in 10 probands in 3 publications (PMIDs: 24387990, 24387991, 28272537) are included in this curation. These variants have been demonstrated to segregate in compound heterozygous or homozygous state in the affected individuals. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss-of-function. This gene-disease association is supported by in-vivo studies in drosophila, in which siRNA-mediated knockdown of PCYT1A led to blindness in drosophila (PMID: 29754800). Immunostaining of endogenous PCYT1A also demonstrated its expression in mouse retina tissue (PMID: 29754800). In summary, PCYT1A is strongly associated with autosomal recessive spondylometaphyseal dysplasia with cone-rod dystrophy. Three patients with nonsyndromic retinal dystrophy and compound heterozygous PCYT1A variants (truncating variant + missense) have also been reported.
Inheritance Pattern: AD
Disease ID:MONDO:0018998
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0012160
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0012160
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Endocrine; Gastrointestinal; Musculoskeletal; Ophthalmologic
Intervention: Cardiovascular; Gastrointestinal; Endocrine
Rationale: Individuals may be affected by manifestations such as early onset dyslipidemia, hepatic steatosis, and insulin-resistant diabetes mellitus, and awareness may enable early identification and management
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PCYT1A variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001312673.2. 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 | 3 | 86 | 1 | 90 | ||
| missense | 5 | 5 | 124 | 15 | 149 | |
| nonsense | 2 | 4 | 4 | 10 | ||
| start loss | 0 | |||||
| frameshift | 5 | 4 | 9 | |||
| splice donor/acceptor (+/-2bp) | 4 | 8 | 12 | |||
| Total | 7 | 18 | 143 | 101 | 1 | 270 |
Highest pathogenic variant AF is 0.00007810902
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001299602.1 | 8 | MANE Select | |
| Ensembl | ENSP00000394617.1 | 8 | MANE Select | |
| RefSeq | NP_005008.2 | 8 | Standard | |
| Ensembl | ENSP00000292823.2 | 8 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Glycerophospholipid metabolism - Homo sapiens (human)
- Choline metabolism in cancer - Homo sapiens (human)
- Phosphonate and phosphinate metabolism - Homo sapiens (human)
- Lamivudine Pathway, Pharmacokinetics/Pharmacodynamics
- Lamivudine Metabolism Pathway
Biological Process
- phosphatidylcholine biosynthetic process
- CDP-choline pathway
Molecular Function
- choline-phosphate cytidylyltransferase activity
- calmodulin binding
- phosphatidylcholine binding
- protein homodimerization activity
Cellular Component
- nuclear envelope
- cytoplasm
- endoplasmic reticulum
- endoplasmic reticulum membrane
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000292823
- Coding exons
- 8
- Length
- 73736
- Individuals with no LoFs
- 125699
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 49
- Defined
- 125748
- p
- 0.000195
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.64 | 145 | 212 | 0.684 | 0.0000127 | 2426 |
| Missense (PolyPhen) | 34 | 77.384 | 0.43937 | 810 | ||
| Synonymous | -0.520 | 87 | 81.0 | 1.07 | 0.00000527 | 677 |
| Loss of Function | 2.06 | 11 | 21.2 | 0.518 | 0.00000142 | 217 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00014 | 0.00012 | rare |
| Latino/Admixed American | 0.000092 | 0.000087 | rare |
| Ashkenazi Jewish | 0.00022 | 0.00020 | rare |
| East Asian | 0.00030 | 0.00027 | rare |
| Finnish | 0.00023 | 0.00023 | rare |
| European (Non-Finnish) | 0.00023 | 0.00021 | rare |
| South Asian | 0.00024 | 0.00023 | rare |
| Other | 0.00021 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Controls phosphatidylcholine synthesis.;
- Disease
- DISEASE: Spondylometaphyseal dysplasia with cone-rod dystrophy (SMDCRD) [MIM:608940]: A disorder characterized by postnatal growth deficiency resulting in profound short stature, rhizomelia with bowing of the lower extremities, platyspondyly with anterior vertebral protrusions, progressive metaphyseal irregularity and cupping with shortened tubular bones, and early-onset progressive visual impairment associated with a pigmentary maculopathy and electroretinographic evidence of cone-rod dysfunction. {ECO:0000269|PubMed:24387990, ECO:0000269|PubMed:24387991}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Intolerance Scores
- LoFtool
- 0.323
- RVIS EVS
- -0.85
- RVIS percentile EVS
- 11.06
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- Indispensability pred.
- N
- Indispensability score
- 0.0213
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |