19-38496466-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1PP5
The NM_000540.3(RYR1):c.6721C>T(p.Arg2241*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000161 in 1,613,720 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). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000540.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| RYR1 | ENST00000359596.8 | c.6721C>T | p.Arg2241* | stop_gained | Exon 41 of 106 | 5 | NM_000540.3 | ENSP00000352608.2 | ||
| RYR1 | ENST00000355481.8 | c.6721C>T | p.Arg2241* | stop_gained | Exon 41 of 105 | 1 | ENSP00000347667.3 | |||
| RYR1 | ENST00000594335.5 | n.172C>T | non_coding_transcript_exon_variant | Exon 2 of 49 | 1 | ENSP00000470927.2 | ||||
| RYR1 | ENST00000599547.6 | n.6721C>T | non_coding_transcript_exon_variant | Exon 41 of 80 | 2 | ENSP00000471601.2 |
Frequencies
GnomAD3 genomes 0.000164 AC: 25AN: 152124Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000155 AC: 39AN: 251116Hom.: 0 AF XY: 0.000133 AC XY: 18AN XY: 135842
GnomAD4 exome AF: 0.000161 AC: 235AN: 1461478Hom.: 0 Cov.: 32 AF XY: 0.000160 AC XY: 116AN XY: 727036
GnomAD4 genome 0.000164 AC: 25AN: 152242Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14AN XY: 74432
ClinVar
Submissions by phenotype
not provided Pathogenic:9
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Observed in homozygous state or with a pathogenic variant on the opposite allele (in trans) in patients in published literature with an RYR1-related myopathy and not observed in homozygous state in controls (McKie et al., 2014; Todd et al., 2015); Identified in a patient in published literature with a second RYR1 variant and history of congenital myopathy with episodes of generalized atypical normokalemic paralysis as a teen (Zhou et al., 2010); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 33333461, 27447704, 25637381, 24951453, 24195946, 22473935, 23553787, 25525159, 26332594, 25127990, 27854218, 26633545, 29298851, 30155738, 26578207, 30609409, 30611313, 31680349, 34426522, 34539730, 25476234, 20080402) -
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Congenital multicore myopathy with external ophthalmoplegia Pathogenic:5
This is a null variant in a gene where loss-of-function is a known mechanism of disease (PVS1_very strong). It is a known variant that has previously been reported as pathogenic 16 times in ClinVar (PM3_strong) and is found in extremely low frequency in gnomAD population database (PM2_supporting). The variant was found in coumpound heterozygous state with NM_000540.3:c.8068-3C>G. -
This variant has been previously reported as disease-causing and was found once in our laboratory in trans with another pathogenic variant [T4709M] in a 25-year-old female with motor delays, tinnitus, vertigo, central hypotonia, peripheral hypertonia, pes cavus, dysmorphisms, microcephaly, ophthalmoplegia, supraventricular tachycardia, scoliosis, lordosis -
PVS1, PM2, PM3 -
Variant summary: RYR1 c.6721C>T (p.Arg2241X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00016 in 251116 control chromosomes (gnomAD). c.6721C>T has been reported in the literature in multiple compound heterozygous individuals affected with RYR-1 related myopathies (e.g. Zhou_2010, Klein_2012, Garibaldi_2019), in addition, the variant was also reported in homozygous state in 6 fetuses presenting as lethal fetal akinesia in one family (McKie_2014). These data indicate that the variant is very likely to be associated with disease. Publications also reported absent allele specific mRNA, and very low levels of RYR1 protein expression in muscle biopsy samples from compound heterozygous patients, providing evidence for nonsense mediated mRNA decay (e.g. Zhou_2010, Garibaldi_2019). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as pathogenic (n=9) / likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
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Malignant hyperthermia, susceptibility to, 1 Pathogenic:3Uncertain:1
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This variant changes 1 nucleotide in exon 41 of the RYR1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. 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: 159856). This variant has been identified in 43/282472 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of RYR1 function due to truncation variants is not an established disease mechanism for autosomal dominant malignant hyperthermia, although it is associated with other phenotype(s) (clinicalgenome.org). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia. -
The variant NM_000540.3:c.6721C>T (chr19:38496466) in RYR1 was detected in 2 heterozygotes out of 58K WGS Icelanders (MAF= 0,002%). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PM2) this variant classifies as likely pathogenic. -
PVS1, PM2, PS4 - supporting -
RYR1-related disorder Pathogenic:2
This sequence change creates a premature translational stop signal (p.Arg2241*) in the RYR1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RYR1 are known to be pathogenic (PMID: 23919265, 25960145, 28818389, 30611313). This variant is present in population databases (rs200563280, gnomAD 0.2%). This premature translational stop signal has been observed in individuals with autosomal recessive congenital myopathy (PMID: 20080402, 22473935, 23553787, 24195946, 24951453). ClinVar contains an entry for this variant (Variation ID: 159856). For these reasons, this variant has been classified as Pathogenic. -
This nonsense variant found in exon 41 of 106 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a compound heterozygous and homozygous change in patients with multi-minicore disease and fetal akinesia deformation sequence syndrome (PMID: 20080402, 34539730, 24951453, 25476234). The c.6721C>T (p.Arg2241Ter) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.015% (43/282472) and is absent in the homozygous state, thus it is presumed to be rare. Based on the available evidence, the c.6721C>T (p.Arg2241Ter) variant is classified as Pathogenic. -
Hydrops fetalis Pathogenic:1
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Neuromuscular disease;C5830701:Central core myopathy Pathogenic:1
The p.Arg2241X variant in RYR1 has been reported in at least 6 individuals with myopathy in the compound heterozygous state (Illingworth 2014, Zhou 2010, Klein 2012, Todd 2018) and in several homozygous affected members of one family with foetal akinesia deformation sequence/lethal multiple pterygium syndrome (McKie 2014). This nonsense variant leads to a premature termination codon at position 2241, which is predicted to lead to a truncated or absent protein. This variant has also been reported in ClinVar (Variation ID 159856). This variant was also identified in 23/10348 of Ashkenazi Jewish and in 18/128888 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org/). However, this frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide further evidence that this variant causes nonsense mediated RNA decay (Zhou 2010). Loss of function in the RYR1 gene is associated with myopathies including central core disease, multi-minicore disease, centronuclear myopathy, and congenital fiber type disproportion. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive RYR1-related myopathy. ACMG/AMP Criteria applied: PVS1, PM3_Very strong, PP1_moderate. -
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 Pathogenic:1
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Central core myopathy Pathogenic:1
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Multi-minicore disease and atypical periodic paralysis Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at