TLCD3B

Chr 16AR

TLC domain containing 3B

Also known as: CORD22, FAM57B, FP1188

NCBI Gene: 83723 ENSG00000149926 UniProt: Q71RH2 OMIM: 615175

The protein is involved in ceramide synthesis and functions as a transmembrane protein that may be targeted by PPAR-gamma. Mutations cause cone-rod dystrophy 22, a retinal degeneration affecting both cone and rod photoreceptors with autosomal recessive inheritance. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.516), suggesting intolerance to complete protein loss.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a transmembrane protein, which may be a likely target of peroxisome proliferator-activated receptor gamma (PPAR-gamma). The product of the orthologous gene in mouse is related to obesity. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.521 OMIM phenotype

Clinical Summary— TLCD3B

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.66) — some intolerance to loss-of-function variants.

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ClinVar Variants

2 unique Pathogenic / Likely Pathogenic· 25 VUS of 35 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.52LOEUF

pLI 0.665

Z-score 2.71

OE 0.16 (0.07–0.52)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.18Z-score

OE missense 0.74 (0.63–0.86)

117 obs / 158.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.16 (0.07–0.52)

0≤0.351.4

Missense OE?0.74 (0.63–0.86)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 2 / 12.2Missense obs/exp: 117 / 158.9Syn Z: -0.01

This gene — mechanism propensity

0.75top 25%

GOF

0.73top 25%

LOF

0.2483th %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

35 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

VUS25

Likely Benign5

Pathogenic

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Synonymous	Total
Pathogenic	1	1	0	2
Likely Pathogenic	0	0	0	0
VUS	1	24	0	25
Likely Benign	0	2	3	5
Benign	0	0	0	0
Total	2	27	3	32

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

View in ClinVar →

281 pathogenic / likely-pathogenic (of 299) ClinVar copy-number / structural variants overlap TLCD3B — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →