NM_000540.3:c.7336G>A
Variant summary
Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM1
The NM_000540.3(RYR1):c.7336G>A(p.Gly2446Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000044 in 1,612,844 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G2446C) 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: Uncertain_significance. The variant received 2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000592 AC: 9AN: 152150Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000478 AC: 12AN: 251008 AF XY: 0.0000589 show subpopulations
GnomAD4 exome AF: 0.0000424 AC: 62AN: 1460694Hom.: 1 Cov.: 31 AF XY: 0.0000523 AC XY: 38AN XY: 726662 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000592 AC: 9AN: 152150Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7AN XY: 74328 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Uncertain:2
RYR1: PM1, PM2, PP3 -
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in a patient with intermittent limb weakness with a second RYR1 variant (Matthews et al., 2018); This variant is associated with the following publications: (PMID: 12668474, 29298851) -
Malignant hyperthermia, susceptibility to, 1 Uncertain:1
This missense variant replaces glycine with serine at codon 2446 of the RYR1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 has been reported in other phenotype(s) (ClinVar variation ID: 544400; PMID: 29298851). This variant has been identified in 13/282372 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. -
RYR1-related disorder Uncertain:1
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2446 of the RYR1 protein (p.Gly2446Ser). This variant is present in population databases (rs375148516, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of periodic paralyisis (PMID: 29298851). ClinVar contains an entry for this variant (Variation ID: 544400). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Central core myopathy Uncertain:1
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Congenital myopathy with fiber type disproportion;C1840365:King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at