PTDSS1

Chr 8AD

phosphatidylserine synthase 1

Also known as: LMHD, PSS1, PSSA

NCBI Gene: 9791 ENSG00000156471 UniProt: P48651 OMIM: 612792

This enzyme catalyzes the formation of phosphatidylserine from phosphatidylcholine or phosphatidylethanolamine through a base-exchange reaction, producing a critical membrane phospholipid involved in cellular structure and signaling. Mutations cause Lenz-Majewski hyperostotic dwarfism, a rare disorder characterized by skeletal abnormalities and overgrowth, with autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants (LOEUF 0.448), indicating it is intolerant to complete protein loss.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene catalyzes the formation of phosphatidylserine from either phosphatidylcholine or phosphatidylethanolamine. Phosphatidylserine localizes to the mitochondria-associated membrane of the endoplasmic reticulum, where it serves a structural role as well as a signaling role. Defects in this gene are a cause of Lenz-Majewski hyperostotic dwarfism. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2014]

GeneReviews OMIM ResearchGenerating clinical summary…

GOFmechanismADLOEUF 0.451 OMIM phenotype

Clinical Summary— PTDSS1

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.25) despite low pLI — interpret in context.

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ClinVar Variants

8 unique Pathogenic / Likely Pathogenic· 105 VUS of 295 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — PTDSS1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.45LOEUF

pLI 0.151

Z-score 3.95

OE 0.25 (0.14–0.45)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.38Z-score

OE missense 0.59 (0.52–0.67)

158 obs / 267.4 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.25 (0.14–0.45)

0≤0.351.4

Missense OE?0.59 (0.52–0.67)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 8 / 32.2Missense obs/exp: 158 / 267.4Syn Z: 0.47

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitivePTDSS1-related Lenz-Majewski hyperostotic dwarfismGOFAD

limitedPTDSS1-related developmental delayOTHERAD

This gene — mechanism propensity

0.6744th %ile

GOF

0.6736th %ile

LOF

0.3551th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function, dominant-negative and loss-of-function). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports gain-of-function. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median · 1 literature citation

DNprediction above median

LOF1 literature citation · LOEUF 0.45

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

GOFGain-of-function mutations in the phosphatidylserine synthase 1 (PTDSS1) gene cause Lenz-Majewski syndrome.1

LOFThis is the first report of the clinical phenotype seen in an individual with a heterozygous loss-of-function variant in PTDSS1.2

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

References

ClinVar Variant Classifications

295 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5

Likely Pathogenic3

VUS105

Likely Benign99

Benign43

Conflicting6

Pathogenic

Likely Pathogenic

105

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	5	0	0	5
Likely Pathogenic	0	3	0	0	3
VUS	8	90	5	2	105
Likely Benign	1	13	38	47	99
Benign	0	5	34	4	43
Conflicting	—				6
Total	9	116	77	53	261

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

View in ClinVar →

38 pathogenic / likely-pathogenic (of 41) ClinVar copy-number / structural variants overlap PTDSS1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →