C9ORF72

Chr 9AD

C9orf72-SMCR8 complex subunit

Also known as: ALSFTD, DENND9, DENNL72, FTDALS, FTDALS1

NCBI Gene: 203228 ENSG00000147894 UniProt: Q96LT7 OMIM: 614260

The C9ORF72 protein functions as a guanine nucleotide exchange factor for Rab GTPases and regulates autophagy, endosomal trafficking, and axon growth in motor neurons. Hexanucleotide repeat expansions in this gene cause frontotemporal dementia and amyotrophic lateral sclerosis, typically with adult onset. Inheritance is autosomal dominant.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene plays an important role in the regulation of endosomal trafficking, and has been shown to interact with Rab proteins that are involved in autophagy and endocytic transport. Expansion of a GGGGCC repeat from 2-22 copies to 700-1600 copies in the intronic sequence between alternate 5' exons in transcripts from this gene is associated with 9p-linked ALS (amyotrophic lateral sclerosis) and FTD (frontotemporal dementia) (PMID: 21944778, 21944779). Studies suggest that hexanucleotide expansions could result in the selective stabilization of repeat-containing pre-mRNA, and the accumulation of insoluble dipeptide repeat protein aggregates that could be pathogenic in FTD-ALS patients (PMID: 23393093). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2016]

GeneReviews OMIM ResearchGenerating clinical summary…

ADLOEUF 0.931 OMIM phenotype

Clinical Summary— C9ORF72

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Gene-Disease Validity (ClinGen)

frontotemporal dementia and/or amyotrophic lateral sclerosis 1 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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

3 unique Pathogenic / Likely Pathogenic· 51 VUS of 104 total submissions

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Clinical Trials

12 active or recruiting trials — potential therapeutic options may be available

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GeneReview available — C9ORF72

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.93LOEUF

pLI 0.000

Z-score 1.82

OE 0.58 (0.38–0.93)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.24Z-score

OE missense 0.96 (0.86–1.06)

240 obs / 250.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.58 (0.38–0.93)

0≤0.351.4

Missense OE?0.96 (0.86–1.06)

0≤0.61.4

Synonymous OE?1.16

0≤1.21.6

LoF obs/exp: 13 / 22.3Missense obs/exp: 240 / 250.9Syn Z: -1.20

ClinVar Variant Classifications

104 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

VUS51

Likely Benign8

Benign23

Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	3	0	3
Likely Pathogenic	0	0	0	0	0
VUS	1	15	31	4	51
Likely Benign	0	2	3	3	8
Benign	0	1	17	5	23
Total	1	18	54	12	85

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

View in ClinVar →

73 pathogenic / likely-pathogenic (of 83) ClinVar copy-number / structural variants overlap C9ORF72 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →