TMEM65

Chr 8

transmembrane protein 65

NCBI Gene: 157378 ENSG00000164983 UniProt: Q6PI78 OMIM: 616609

TMEM65 encodes a protein essential for maintaining cardiac intercalated disc structure and function, stabilizing gap junction and sodium channel localization, and regulating mitochondrial respiration. Mutations cause autosomal recessive arrhythmogenic cardiomyopathy with conduction defects and sudden cardiac death in infancy and childhood. The protein's critical role in cardiac conduction system development and function makes this a severe early-onset cardiac condition requiring immediate cardiology management.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to be involved in cardiac conduction; cardiac ventricle development; and regulation of cardiac conduction. Located in several cellular components, including intercalated disc; mitochondrial inner membrane; and nucleolus. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 0.83

Clinical Summary— TMEM65

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Gene-Disease Validity (ClinGen)

mitochondrial disease · ARLimited

Limited evidence — not for standalone diagnostic reporting

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.32) despite low pLI — interpret in context.

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ClinVar Variants

22 VUS of 38 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?

0.83LOEUF

pLI 0.111

Z-score 1.91

OE 0.32 (0.15–0.83)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.38Z-score

OE missense 0.60 (0.49–0.75)

58 obs / 96.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.32 (0.15–0.83)

0≤0.351.4

Missense OE?0.60 (0.49–0.75)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 3 / 9.3Missense obs/exp: 58 / 96.2Syn Z: 0.13

This gene — mechanism propensity

0.76top 25%

GOF

0.5366th %ile

LOF

0.3261th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction 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

38 submitted variants in ClinVar

ClinVar

Classification Summary

VUS22

Likely Benign6

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	22	0	0	22
Likely Benign	3	1	2	6
Benign	0	0	0	0
Total	25	1	2	28

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

View in ClinVar →

51 pathogenic / likely-pathogenic (of 57) ClinVar copy-number / structural variants overlap TMEM65 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →