HSDL1

Chr 16

hydroxysteroid dehydrogenase like 1

Also known as: SDR12C3

NCBI Gene: 83693 ENSG00000103160 UniProt: Q3SXM5 OMIM: 619067

HSDL1 encodes a hydroxysteroid dehydrogenase-like protein localized to intermediate filaments and mitochondria. Mutations cause autosomal recessive developmental and epileptic encephalopathy with onset in infancy, characterized by severe intellectual disability, seizures, and progressive neurodegeneration. The gene shows tolerance to loss-of-function variants in the general population (pLI 0.003), suggesting the pathogenic variants may have specific effects on protein function.

OMIM ResearchSummary from RefSeq

Located in intermediate filament cytoskeleton and mitochondrion. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.92

Clinical Summary— HSDL1

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 54 VUS of 68 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.92LOEUF

pLI 0.003

Z-score 1.79

OE 0.46 (0.25–0.92)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-1.08Z-score

OE missense 1.22 (1.09–1.36)

233 obs / 191.1 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.46 (0.25–0.92)

0≤0.351.4

Missense OE?1.22 (1.09–1.36)

0≤0.61.4

Synonymous OE?1.60

0≤1.21.6

LoF obs/exp: 6 / 12.9Missense obs/exp: 233 / 191.1Syn Z: -4.06

This gene — mechanism propensity

0.80top 10%

GOF

0.6443th %ile

LOF

0.2190th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

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.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

68 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

VUS54

Likely Benign3

Benign2

Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Total
Pathogenic	0	1	1
Likely Pathogenic	0	0	0
VUS	54	0	54
Likely Benign	2	1	3
Benign	0	2	2
Total	56	4	60

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

View in ClinVar →

45 pathogenic / likely-pathogenic (of 78) ClinVar copy-number / structural variants overlap HSDL1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →