rs118192174
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PP2PP3_StrongPP5
The NM_000540.3(RYR1):c.7268T>A(p.Met2423Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000409 in 1,612,200 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000043 ( 0 hom. )
Consequence
RYR1
NM_000540.3 missense
NM_000540.3 missense
Scores
11
4
2
Clinical Significance
Conservation
PhyloP100: 8.00
Genes affected
RYR1 (HGNC:10483): (ryanodine receptor 1) This gene encodes a ryanodine receptor found in skeletal muscle. The encoded protein functions as a calcium release channel in the sarcoplasmic reticulum but also serves to connect the sarcoplasmic reticulum and transverse tubule. Mutations in this gene are associated with malignant hyperthermia susceptibility, central core disease, and minicore myopathy with external ophthalmoplegia. Alternatively spliced transcripts encoding different isoforms have been described. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000540.3
PP2
?
Missense variant where missense usually causes diseases, RYR1
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.955
PP5
?
Variant 19-38499961-T-A is Pathogenic according to our data. Variant chr19-38499961-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 12989.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Pathogenic=5, Uncertain_significance=1, not_provided=1}. Variant chr19-38499961-T-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.7268T>A | p.Met2423Lys | missense_variant | 45/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.7268T>A | p.Met2423Lys | missense_variant | 45/106 | 5 | NM_000540.3 | A2 | |
RYR1 | ENST00000355481.8 | c.7268T>A | p.Met2423Lys | missense_variant | 45/105 | 1 | P4 | ||
RYR1 | ENST00000594335.5 | c.722T>A | p.Met241Lys | missense_variant, NMD_transcript_variant | 6/49 | 1 | |||
RYR1 | ENST00000599547.6 | c.7268T>A | p.Met2423Lys | missense_variant, NMD_transcript_variant | 45/80 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000199 AC: 3AN: 151008Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251410Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135898
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GnomAD4 exome AF: 0.0000431 AC: 63AN: 1461192Hom.: 0 Cov.: 36 AF XY: 0.0000523 AC XY: 38AN XY: 726870
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:9Uncertain:1Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:2Other:1
not provided, no classification provided | literature only | Leiden Muscular Dystrophy (RYR1) | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 12, 2022 | - - |
RYR1-related disorder Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | DASA | Jun 10, 2022 | The c.7268T>A;p.(Met2423Lys) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 12989; OMIM: 180901.0027; PMID: 17483490; 17365175; 17033962; 16380615) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (central region) - PM1. The variant is present at low allele frequencies population databases (rs118192174– gnomAD 0.0001987%; ABraOM no frequency - http://abraom.ib.usp.br/) -PM2_supporting. The variant co-segregated with disease in multiple affected family members (PMID: 17033962; PMID: 16380615) - PP1_strong. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is Pathogenic - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2024 | This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 2423 of the RYR1 protein (p.Met2423Lys). This variant is present in population databases (rs118192174, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive congenital myopathy (PMID: 17033962, 18253926, 21911697, 30611313). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12989). 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 80%. For these reasons, this variant has been classified as Pathogenic. - |
Congenital multicore myopathy with external ophthalmoplegia Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2012 | - - |
Neuromuscular disease Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 21, 2023 | The p.Met2423Lys variant in RYR1 has been reported as compound heterozygous in at least 3 individuals with minicore myopathy or Dusty core disease and segregated with disease in 2 affected relatives from 1 family (Jungbluth 2005 PMID: 16380615, Zhou 2006 PMID: 17033962, Zhou 2007 PMID: 17483490, Monnier 2008 PMID: 18253926, Klein 2012 PMID: 21911697, Garibaldi 2019 PMID: 30611313). The p.Met2423Lys variant has also been identified in 0.02% (1/4672) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). Please note that for diseases with clinical variability, reduced penetrance, or recessive inheritance, pathogenic variants may be present at a low frequency in the general population. Computational prediction tools and conservation analysis suggest that the p.Met2423Lys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, the p.Met2423Lys variant is likely pathogenic for minicore myopathy in an autosomal recessive manner based upon reports of this variant in trans with pathogenic variants and segregation studies. ACMG/AMP criteria applied: PM3_Strong, PP1, PP3. - |
Congenital myopathy with fiber type disproportion Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2016 | This variant was classified as: Pathogenic. - |
Clubfoot;C0476403:EMG abnormality;C4024921:Lower limb amyotrophy Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Mar 18, 2016 | - - |
Congenital myopathy with fiber type disproportion;C0751951:Central core myopathy;C1840365:King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 28, 2021 | - - |
Malignant hyperthermia, susceptibility to, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 13, 2023 | This missense variant replaces methionine with lysine at codon 2423 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with autosomal dominant malignant hyperthermia in the literature, although it is associated with other phenotype(s) (ClinVar variation ID: 12989). This variant has been identified in 5/251410 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Benign
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
A;A;A
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Uncertain
D;D
Polyphen
D;P
Vest4
MVP
MPC
0.48
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at