19-38584989-T-C
Variant summary
Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_000540.3(RYR1):c.14693T>C(p.Ile4898Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance,drug response (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I4898S) has been classified as Uncertain significance.
Frequency
Consequence
NM_000540.3 missense
Scores
Clinical Significance
Conservation
Publications
- malignant hyperthermia, susceptibility to, 1Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, Ambry Genetics
- congenital multicore myopathy with external ophthalmoplegiaInheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
- RYR1-related myopathyInheritance: AR, AD Classification: DEFINITIVE Submitted by: ClinGen
- central core myopathyInheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
- King-Denborough syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- malignant hyperthermia of anesthesiaInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- autosomal recessive centronuclear myopathyInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- benign Samaritan congenital myopathyInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- congenital myopathy with myasthenic-like onsetInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- lethal multiple pterygium syndromeInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Likely_pathogenic. The variant received 8 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| RYR1 | NM_000540.3 | c.14693T>C | p.Ile4898Thr | missense_variant | Exon 102 of 106 | ENST00000359596.8 | NP_000531.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| RYR1 | ENST00000359596.8 | c.14693T>C | p.Ile4898Thr | missense_variant | Exon 102 of 106 | 5 | NM_000540.3 | ENSP00000352608.2 |
Frequencies
GnomAD3 genomes
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461838Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727218 show subpopulations
Age Distribution
GnomAD4 genome
ClinVar
Submissions by phenotype
not provided Pathogenic:3Other:1
Published functional studies demonstrate a damaging effect as this variant results in altered calcium conductance, with little to no calcium release, reduced luminal calcium storage, and increased cytoplasmic calcium levels (PMID: 10097181); Mouse model study demonstrates I4898T results in absent voltage-induced calcium release (PMID: 22203976); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15175001, 15299003, 21825032, 29629541, 16084090, 32403337, 20961389, 20461000, 12642598, 11274444, 12161072, 25084811, 27363342, 11741831, 11709545, 24561095, 35428369, 32721234, 18003898, 33458582, 32140910, 34008892, 25214167, 35693006, 20681998, 33767344, 19959667, 32528171, 33333461, 20888934, 22203976, 10097181)
Malignant hyperthermia, susceptibility to, 1 Pathogenic:2Uncertain:1
PM1, PM2, PP3, PP4, PP5
The ClinGen RYR1-MHS variant curation expert panel is focused on assessing variants in RYR1 for pathogenicity as related to malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions. This sequence variant predicts a substitution of Isoleucine with Threonine at codon 4898 of the RYR1 protein, p.(Ile4898Thr). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in individuals with a personal or family history of an MH episode or central core disease but without sufficient information to consider the reports for informing PS4 in relation to MHS inherited in an autosomal dominant pattern (PMID: 10097181, 11709545, 12565913, 16621918 and others). Functional studies in HEK293 cells do not show an increased sensitivity to RYR1 agonists, BS3_Supporting (PMID:10097181). Additional functional studies were published for this variant that did not show statistical differences in resting Ca2+ and sarcoplasmic reticulum Ca2+ content, however, those assays were not considered standard assays for variant interpretation in regard to MHS by the ClinGen RYR1 VCEP (PMID:11274444, PMID: 12642598). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Supporting (PMID: 21118704). A REVEL score >0.85 supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance in relation to MHS inherited in an autosomal dominant pattern. Criteria implemented: PM1_Sup, PP3_Moderate, BS3_Supporting.
Central core myopathy Pathogenic:2Other:1
RYR1-related disorder Pathogenic:1
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 4898 of the RYR1 protein (p.Ile4898Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant central core disease (CCD) (PMID: 10097181, 11709545, 11741831, 20888934, 24561095, 25084811). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is also known as I4897T. ClinVar contains an entry for this variant (Variation ID: 12975). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RYR1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects RYR1 function (PMID: 10097181, 12642598, 15175001, 21825032, 22203976). For these reasons, this variant has been classified as Pathogenic.
RYR1-related myopathy Pathogenic:1
This variant is absent from gnomAD v4 (adequate coverage >20X confirmed) and an internal database of 1074 control alleles. PP2 Not Met: missense Z-score is 1.918. PP3_Strong: REVEL score is 0.943. PM1 Met: variant occurs in exon 102 which is in a C-terminal hotspot region where other pathogenic variants are found (between codons 4136 and 4973, exons 85-104) (PMID 18564801). PM5 Met: NM_000540.3(RYR1):c.14693T>C (p.Ile4898Thr) classified as pathogenic (ClinVar VCV000012975.41). PS4_Supporting: heterozygous observation of variant in 1 proband with relevant phenotype (SCV000852451.1).
Congenital myopathy with fiber type disproportion;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy Pathogenic:1
Congenital myopathy Pathogenic:1
The heterozygous p.Ile4898Thr variant in RYR1 was identified by our study in 1 individual with congenital myopathy. The p.Ile4898Thr variant in RYR1 has been reported in at least 7 families with congenital myopathy, segregated with disease in 26 affected relatives from 2 families (PMID: 10097181, PMID: 11741831), and has been identified in 0.00008% (1/1179980) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs118192170). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 12975) and has been interpreted as pathogenic by multiple submitters for congenital myopathy, and as a variant of uncertain significance by the ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel. This variant was found to be de novo in monozygotic twins with confirmed paternity and maternity (PMID: 20888934). The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. In vitro functional studies provide some evidence that the p.Ile4898Thr variant may slightly impact protein function (PMID: 10097181, 11741831). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The number of missense variants reported in RYR1 in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant congenital myopathy. ACMG/AMP Criteria applied: PP1_strong, PP3_moderate, PS4_moderate, PP2, PM2_supporting PS2_supporting, PS3_supporting (Richards 2015).
methoxyflurane response - Toxicity Other:1
PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Toxicity
enflurane response - Toxicity Other:1
PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Toxicity
halothane response - Toxicity Other:1
PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Toxicity
desflurane response - Toxicity Other:1
PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Toxicity
succinylcholine response - Toxicity Other:1
PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Toxicity
sevoflurane response - Toxicity Other:1
PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Toxicity
isoflurane response - Toxicity Other:1
PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Toxicity
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at