GIPC3

Chr 19AR

GIPC PDZ domain containing family member 3

Also known as: C19orf64, DFNB15, DFNB72, DFNB95

NCBI Gene: 126326 ENSG00000179855 UniProt: Q8TF64 OMIM: 608792

GIPC3 encodes a protein required for postnatal maturation of hair bundles and long-term survival of hair cells and spiral ganglion in the inner ear. Mutations cause autosomal recessive deafness 15, with inheritance following an autosomal recessive pattern. The gene shows low constraint to loss-of-function variants (pLI 0.009, LOEUF 0.934), consistent with the recessive inheritance pattern observed clinically.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene belongs to the GIPC family. Studies in mice suggest that this gene is required for postnatal maturation of the hair bundle and long-term survival of hair cells and spiral ganglion in the ear. Mutations in this gene are associated with autosomal recessive deafness. [provided by RefSeq, Dec 2011]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.931 OMIM phenotype

Clinical Summary— GIPC3

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Gene-Disease Validity (ClinGen)

nonsyndromic genetic hearing loss · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

28 unique Pathogenic / Likely Pathogenic· 115 VUS of 274 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?

0.93LOEUF

pLI 0.009

Z-score 1.73

OE 0.44 (0.23–0.93)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.18Z-score

OE missense 0.96 (0.85–1.09)

173 obs / 179.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.44 (0.23–0.93)

0≤0.351.4

Missense OE?0.96 (0.85–1.09)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 5 / 11.3Missense obs/exp: 173 / 179.7Syn Z: -0.08

This gene — mechanism propensity

0.6841th %ile

GOF

0.6540th %ile

LOF

0.3356th %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

274 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic14

Likely Pathogenic14

VUS115

Likely Benign92

Benign19

Conflicting16

Pathogenic

Likely Pathogenic

115

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	8	5	1	0	14
Likely Pathogenic	10	4	0	0	14
VUS	3	103	7	2	115
Likely Benign	1	8	36	47	92
Benign	0	0	18	1	19
Conflicting	—				16
Total	22	120	62	50	270

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

View in ClinVar →

19 pathogenic / likely-pathogenic (of 27) ClinVar copy-number / structural variants overlap GIPC3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →