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HSERVPRODH

Chr 22

human-specific endogenous retroviral insert PRODH enhancer

Also known as: hsERV_PRODH

NCBI Gene: 106660608

HSERVPRODH is a regulatory enhancer sequence that controls expression of the PRODH gene, which encodes proline dehydrogenase, an enzyme that catalyzes the first step in proline catabolism. Mutations in the PRODH gene (not this enhancer region itself) cause hyperprolinemia type I, an autosomal recessive metabolic disorder that can present with seizures, intellectual disability, and behavioral problems. This enhancer region represents a human-specific regulatory element derived from an ancient retroviral sequence.

ResearchSummary from RefSeq

This region includes an endogenous retrovirus long-terminal repeat (LTR)-derived sequence that binds SRY (sex determining region Y)-box 2 (SOX2) and functions as an enhancer of the proline dehydrogenase (oxidase) 1 (PRODH) gene in Tera-1 (testicular embryonal germ cell tumor) cells. The LTR sequence acts synergistically with a CG-rich region downstream of the transcription start site to promote expression of the PRODH gene. Cytosine methylation of the LTR element but not the CG-region can prevent enhancer activity. The orthologous sequence in chimpanzee does not function as an enhancer, suggesting that regulation by this region is human-specific. A subregion of the LTR element was also validated as a functional enhancer by Sharpr-MPRA (Systematic high-resolution activation and repression profiling with reporter tiling using massively parallel reporter assays) in HepG2 liver carcinoma cells (group: HepG2 Activating non-DNase unmatched - State 3:PromF, promoter flanking), but the same subregion displayed repressive activity by Sharpr-MPRA in K562 erythroleukemia cells (group: K562 Repressive non-DNase unmatched - State 22:ReprW, weaker Polycomb repression). A subregion was also shown to be an enhancer by the ChIP-STARR-seq massively parallel reporter assay in naive human embryonic stem cells, where it associates with the OCT4 and NANOG transcription factors and is marked by the H3K27ac histone modification. [provided by RefSeq, Dec 2022]

ResearchGenerating clinical summary…

Clinical Summary— HSERVPRODH

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ClinVar Variants

4 unique Pathogenic / Likely Pathogenic· 5 VUS of 14 total submissions

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Some data sources returned errors (2)

ensembl: Error: Ensembl fetch failed: 400 for /lookup/symbol/homo_sapiens/HSERVPRODH?content-type=application/json&expand=1

gnomad: Error: Gene not found

Population Genetics & Constraint

gnomAD

Constraint data not available from gnomAD.

ClinVar Variant Classifications

14 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

Likely Pathogenic2

VUS5

Likely Benign3

Benign2

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	2	0	2
Likely Pathogenic	2	0	0	2
VUS	1	4	0	5
Likely Benign	0	0	3	3
Benign	0	2	0	2
Total	3	8	3	14

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

183 pathogenic / likely-pathogenic (of 200) ClinVar copy-number / structural variants overlap HSERVPRODH — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →