ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

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Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
Loss of function variants in RYR1 have been implicated in autosomal recessive and autosomal dominant diseases. The autosomal recessive conditions include congenital fiber-type disproportion (CFTD) (10-20% of cases) and Multiminicore disease (MmD), especially cases associated with ophthalmoplegia (in a small minority of cases). The variants in these diseases are mostly missense mutations, not large deletions or duplications. Autosomal dominantly-inherited conditions include Central Core Disease (CCD) and malignant hyperthermia susceptibility (MHS). Most autosomal dominant cases of CCD are also associated with variants in RYR1, but notably there also have been reported occurrences of autosomal recessive variants in RYR1 for this condition. Rossi et al 2006 (PMID 17293538) reported a family with a single-nucleotide deletion in exon 100 that led to a deletion of the last 202 amino acids (p.R4837fsX4839). Although the father and his two daughters were all confirmed to have this mutation, only he was clinically affected based upon the standard in vitro contracture test (IVCT). Of note, however, the daughters did have the same histologic changes in the skeletal muscle fibers so their lack of clinical findings could be due to reduced penetrance. Monnier et al 2001 (PMID 11709545) identified three in-frame amino acid deletions (c.12640 del9nt, c.13938 del6nt, and c.14578 delttc) that led to CCD in three multi-generation families meeting clinical criteria and histologic findings in skeletal muscles. None of the mutations was found in 100 unrelated chromosomes from the general population. In up to 70-80% of cases of MHS, variants in RYR1 are believed to be causative. Most mutations associated with MHS are single nucleotide substitutions, but a single amino acid deletion resulting in deletion of a conserved glutamic acid at position 2347 (p.G2347del) was reported as the first deletion mutation. Sambuughin et al 2001 (PMID 11389482) identified this in two unrelated families with this mutation in multiple affected family members. Interestingly, the same variant was observed in autosomal dominant MHS and autosomal recessive lethal neonatal hypotonia in the same family. Monnier et al 2009 (PMID 19734047) described a child with lethal neonatal hypotonia who had compound heterozygosity for mutations in RYR1 including p.Lys929_Ser3713delinsAsn (leading to an in-frame large deletion extending from exon 23 to exon 76) and a non-synonymous p.Ser2279dup, exon 42. Given that both parents were confirmed carriers, each for one of the mutations, and were unaffected, these were presumed to be recessive mutations for the neonatal hypotonia. However, the father who was the confirmed p.Ser2279dup carrier was found by IVCT to meet diagnostic criteria for autosomal dominantly inherited MHS trait.

Evidence for Triplosenstive Phenotype

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.