CHRM3

Gene Facts

• HGNC Symbol: CHRM3 (HGNC:1952)
• HGNC Name: cholinergic receptor muscarinic 3
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: No previous names found
• Alias symbols: m3AChR
• %HI: 33.36
• pLI: 1
• LOEUF: 0.42
• Cytoband: 1q43
• Genomic Coordinates:

  GRCh37/hg19:	chr1:239549868-240078750
  GRCh38/hg38:	chr1:239386568-239915450

• MANE Select Transcript: NM_001375978.1 ENST00000676153.1
• Function: The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is Pi turnover. {ECO:0000269|PubMed:7565628}. (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-21837
• ClinGen Curation ID: CCID:006865
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: No Evidence for Haploinsufficiency (0)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 11/16/2023

Haploinsufficiency (HI) Score Details

• HI Score: 0
• HI Evidence Strength: No Evidence for Haploinsufficiency
• HI Evidence Comments: CHRM3 encodes for the M3-muscarinic receptor, which is one of five G protein-linked 7-transmembrane muscarinic receptors expressed in the CNS and peripheral tissues. Given the current limited and contradictory evidence for CHRM3 haploinsufficiency, the haploinsufficiency score for this gene is 0. There is limited evidence to support the AR inheritance as well. The following papers were reviewed and not scored: Petersen, et al. (PMID: 23253743) report a 3 1/2 year old male who presented with autism features, intellectual disabilities, strabismus, and cranial nerve VI palsy. He had a prominent nasal bridge and behavior problems. The patient was found to carry a 473 kb deletion that removed the first four exons of CHRM3. This case is not being scored because no functional/expression studies were performed, and parental studies were not available. Kushima I, et al. (PMID:27240532) performed a high-resolution genome-wide CNV analysis on a mainly (92%) Japanese population (1699 schizophrenia cases and 824 controls) and identified 7066 rare CNVs, 70.0% of which were small (<100 kb). A 23 Kb intergenic deletion of CHRM3 gene was listed in table s13 as a clinically significant CNV which was significantly more frequent in cases than in controls (odds ratio = 3.04, P = 9.3 × 10E-9, 9.0% of cases). The 56 yo female patient had schizophrenia and the history of ID/DD and autism. The deletion does not include any coding sequence in primary transcript NM_000740. Cheng X, et al. (PMID:31019551) report on a patient with intellectual disability and a 763.3 Kb de novo duplication on 1q43 which includes 5' UTR and first 2 exons of CHRM3. It was detected by next generation sequencing (NGS) and no further confirmation test was performed. The patient presented with intellectual disability, developmental delay, autistic behavior, limited or no speech, social withdrawal, self-injurious, feeding difficulties, strabismus, short stature, hand anomalies, and no seizures, anxiety, or mood swings, and clinodactyly. It is unclear if these first 2 exons are coding exons. A small non-focal deletion (911 kb) that encompasses all of CHRM3 and most of FMN2 (Perrone et al. 2011). Shared phenotypic findings among the patients in these studies include autistic features, intellectual disabilities. The patient carrying the 911 kb deletion presented with additional phenotypic abnormalities including cryptorchidism and short stature. However, Weber et al. (PMID:22077972) report a Turkish family with 6 male siblings affected by prune belly-like features. Two had full prune belly syndrome, 4 had bladder malformations, and 3 had posterior urethral valves. They all also had bilaterally impaired pupillary constriction to light and dry mouths. Affected individuals were homozygous for a frameshift variant in CHRM3. Of note, the heterozygous parents and sister were unaffected and the variant was not found in 374 Turkish control chromosomes. Authors comment that this phenotype is consistent with a null mouse model. Furthermore, Liu X et al. (PMID:36046230) performed a study of genes associated with Intrahepatic cholestasis of pregnancy (ICP) in 249 individuals and 1,029 local control individuals by using whole-exome sequencing. A novel nonsense variant in CHRM3 gene was reported in one patient. There was no additional phenotypic information provided. Last, Lin et al. (PMID:22899762) investigated possible associations between copy number variation involving the CHRM genes (including CHRM3) and high myopia in two different groups of Han Chinese medical students. Using qPCR, no associations with copy loss were found but they did report 23 of the 519 total subjects (4.4%) who had a single copy of CHRM3.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity
• TS Evidence Comments: Reports of focal duplications of CHRM3 have not been reported in clinical patients. Lin, et al., (PMID:22899762) report a significant association between copy number gains (3-5 copies) of CHRM3 and high myopia in Han Chinese medical students, indicating that gain of CHRM3 may be a risk factor for high myopia.