SMS

Chr XADIsolated casesXLR

spermine synthase

Also known as: MRSR, MRXSSR, SPMSY, SRS, SpS

NCBI Gene: 6611 ENSG00000102172 UniProt: P52788 OMIM: 182290

This gene encodes spermidine/spermine synthase, which catalyzes the production of spermine from spermidine and decarboxylated S-adenosylmethionine. Mutations cause X-linked recessive Snyder-Robinson syndrome (intellectual developmental disorder) and autosomal dominant Smith-Magenis syndrome, both presenting with intellectual disability and syndromic features. The gene is highly constrained against loss-of-function variants (pLI 0.97, LOEUF 0.31), indicating critical cellular function.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a protein belonging to the spermidine/spermin synthase family and catalyzes the production of spermine from spermidine. Pseudogenes of this gene are located on chromosomes 1, 5, 6 and X. Mutations in this gene cause an X-linked intellectual disability called Snyder-Robinson Syndrome (SRS). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2017]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismAD/Isolated cases/XLRLOEUF 0.302 OMIM phenotypes

Clinical Summary— SMS

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Gene-Disease Validity (ClinGen)

syndromic X-linked intellectual disability Snyder type · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.97). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

34 unique Pathogenic / Likely Pathogenic· 94 VUS of 256 total submissions

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Clinical Trials

9 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — SMS

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.30LOEUF

pLI 0.973

Z-score 3.42

OE 0.06 (0.02–0.30)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.32Z-score

OE missense 0.46 (0.37–0.56)

66 obs / 144.3 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.06 (0.02–0.30)

0≤0.351.4

Missense OE?0.46 (0.37–0.56)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 1 / 15.5Missense obs/exp: 66 / 144.3Syn Z: -0.29

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongSMS-related Snyder-Robinson syndromeLOFXLR

This gene — mechanism propensity

0.2997th %ile

GOF

0.3094th %ile

LOF

0.65top 25%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.30 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

256 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic17

Likely Pathogenic17

VUS94

Likely Benign24

Benign34

Conflicting4

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	9	7	0	17
Likely Pathogenic	3	14	0	0	17
VUS	3	82	9	0	94
Likely Benign	0	2	7	15	24
Benign	0	1	27	6	34
Conflicting	—				4
Total	7	108	50	21	190

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

View in ClinVar →

76 pathogenic / likely-pathogenic (of 83) ClinVar copy-number / structural variants overlap SMS — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

SMS · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

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GeneReview available — SMS

Authoritative clinical overview · NCBI Bookshelf · Recommended first read

Open GeneReview ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Advanced Solid Tumor

Dose Escalation Study of Immunomodulatory Nanoparticles

ACTIVE NOT RECRUITING

NCT04751786Phase PHASE1Radboud University Medical CenterStarted 2021-01-11

PRECIOUS-01

Smith-Magenis Syndrome (SMS)

Natural History Study of Smith-Magenis Syndrome

ACTIVE NOT RECRUITING

NCT00013559National Human Genome Research Institute (NHGRI)Started 2001-03-19

Colorectal Neuroendocrine Tumor G1Gastric Neuroendocrine Tumor G1Neuroendocrine Neoplasm

Octreotide Acetate and Recombinant Interferon Alfa-2b or Bevacizumab in Treating Patients With Metastatic or Locally Advanced, High-Risk Neuroendocrine Tumor

ACTIVE NOT RECRUITING

NCT00569127Phase PHASE3National Cancer Institute (NCI)Started 2007-12-01

BevacizumabLaboratory Biomarker AnalysisOctreotide Acetate

Somatic Mutation

SMS - Study of Somatic Mutations Using Genome Sequencing

ENROLLING BY INVITATION

NCT06851052The Wellcome Sanger InstituteStarted 2016-10-01

sample collectionSeeking consentSample Collection: Surgical

Alzheimer Disease

Does EVOO Induce Gene and Metabolic Changes in Healthy Subjects

ACTIVE NOT RECRUITING

NCT05929924Phase NAAugusta UniversityStarted 2023-08-01