19-38496466-C-T

Variant names:

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

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

RYR1
NM_000540.3 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:23U:1B:1

Conservation

PhyloP100: 3.81

Variant links:

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]

RYR1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 19-38496466-C-T is Pathogenic according to our data. Variant chr19-38496466-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 159856.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=18, Likely_benign=1, Likely_pathogenic=1}. Variant chr19-38496466-C-T is described in Lovd as [Pathogenic]. Variant chr19-38496466-C-T is described in Lovd as [Likely_pathogenic]. Variant chr19-38496466-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3 link	c.6721C>T	p.Arg2241*	stop_gained	Exon 41 of 106	ENST00000359596.8	NP_000531.2	P21817-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RYR1	ENST00000359596.8 link	c.6721C>T	p.Arg2241*	stop_gained	Exon 41 of 106	5	NM_000540.3	ENSP00000352608.2	P21817-1
RYR1	ENST00000355481.8 link	c.6721C>T	p.Arg2241*	stop_gained	Exon 41 of 105	1		ENSP00000347667.3	P21817-2
RYR1	ENST00000594335.5 link	n.172C>T		non_coding_transcript_exon_variant	Exon 2 of 49	1		ENSP00000470927.2	M0R014
RYR1	ENST00000599547.6 link	n.6721C>T		non_coding_transcript_exon_variant	Exon 41 of 80	2		ENSP00000471601.2	M0R127

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000155

AC:

AN:

251116

Hom.:

AF XY:

0.000133

AC XY:

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00219

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000161

AC:

235

AN:

1461478

Hom.:

Cov.:

AF XY:

0.000160

AC XY:

116

AN XY:

727036

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00210

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000151

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000164

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00230

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000264

Hom.:

Bravo

AF:

0.000155

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000165

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:23Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	May 26, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 12, 2022	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) -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 19, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 05, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 18, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 19, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jun 01, 2016	- -

Congenital multicore myopathy with external ophthalmoplegia

Pathogenic:5

Pathogenic, criteria provided, single submitter	research	Cytogenetics and Genomics Lab, Cyprus Institute Of Neurology and Genetics	Jul 20, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 06, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Apr 08, 2024	PVS1, PM2, PM3 -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 23, 2013	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 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 05, 2014	- -

Malignant hyperthermia, susceptibility to, 1

Pathogenic:3Uncertain:1

Pathogenic, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 01, 2013	- -
Likely pathogenic, no assertion criteria provided	research	deCODE genetics, Amgen	Jul 21, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Apr 02, 2020	PVS1, PM2, PS4 - supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 11, 2024	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. -

RYR1-related disorder

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 13, 2025	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. -

Hydrops fetalis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Reproductive Medicine, Peking University Third Hospital

Oct 16, 2019

- -

Neuromuscular disease;C5830701:Central core myopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 08, 2019

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 27, 2021

- -

Central core myopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital

Feb 28, 2020

- -

Multi-minicore disease and atypical periodic paralysis

Benign:1

Likely benign, flagged submission

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.63

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.96

Vest4

0.97

GERP RS

4.9

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over