19-38496466-C-T

Position:

• chr19-38496466-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_000540.3(RYR1):​c.6721C>T​(p.Arg2241Ter) 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:22 U:1 B:1
• Conservation: PhyloP100: 3.81

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]

ACMG classification

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: {Likely_pathogenic=1, Uncertain_significance=1, Pathogenic=17}. 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/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.6721C>T	p.Arg2241Ter	stop_gained	41/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.6721C>T	p.Arg2241Ter	stop_gained	41/106	5	NM_000540.3	ENSP00000352608	A2
RYR1	ENST00000355481.8	c.6721C>T	p.Arg2241Ter	stop_gained	41/105	1		ENSP00000347667	P4
RYR1	ENST00000594335.5	c.175C>T	p.Arg59Ter	stop_gained, NMD_transcript_variant	2/49	1		ENSP00000470927
RYR1	ENST00000599547.6	c.6721C>T	p.Arg2241Ter	stop_gained, NMD_transcript_variant	41/80	2		ENSP00000471601

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152124 Hom.: 0 Cov.: 32

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: 39 AN: 251116 Hom.: 0 AF XY: 0.000133 AC XY: 18 AN XY: 135842

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.: 0 Cov.: 32 AF XY: 0.000160 AC XY: 116 AN XY: 727036

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: 25 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74432

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.: 0

Bravo AF: 0.000155

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000165 AC: 20

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:22 Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:9

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	AiLife Diagnostics, AiLife Diagnostics	May 26, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 18, 2022	- -
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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
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	- -
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) -

Congenital multicore myopathy with external ophthalmoplegia Pathogenic:4

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, no assertion criteria provided	literature only	OMIM	Dec 05, 2014	- -
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, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Apr 08, 2024	PVS1, PM2, PM3 -

Malignant hyperthermia, susceptibility to, 1 Pathogenic:3 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 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. -
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 -
Pathogenic, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 01, 2013	- -

RYR1-related disorder Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 21, 2024	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. -
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. -

Hydrops fetalis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Reproductive Medicine, Peking University Third Hospital

Oct 16, 2019

- -

Neuromuscular disease;C0751951: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. -

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

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 27, 2021

- -

Multi-minicore disease and atypical periodic paralysis Benign:1

Likely benign, no assertion criteria provided

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	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	48
DANN	Uncertain	1.0
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.96	D
MutationTaster	Benign	1.0	A;A;A
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

Other links and lift over

dbSNP: rs200563280; hg19: chr19-38987106; COSMIC: COSV62094830;