rs193922815

chr19-38500637-G-Achr19-38500637-G-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM5 PP2 PP3_Strong PP5_Strong

The NM_000540.3(RYR1):c.7355G>A(p.Arg2452Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,334 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 Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2452P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:4 O:1
• Conservation: PhyloP100: 9.99

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 Pathogenic. Variant got 13 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000540.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-38500636-C-T is described in ClinVar as [Likely_pathogenic, drug_response]. Clinvar id is 65979.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP2: Missense variant where missense usually causes diseases, RYR1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973
• PP5: Variant 19-38500637-G-A is Pathogenic according to our data. Variant chr19-38500637-G-A is described in ClinVar as [Uncertain_significance]. Clinvar id is 133201.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Likely_pathogenic=1, Uncertain_significance=4, not_provided=1}. Variant chr19-38500637-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.7355G>A	p.Arg2452Gln	missense_variant	46/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.7355G>A	p.Arg2452Gln	missense_variant	46/106	5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.7355G>A	p.Arg2452Gln	missense_variant	46/105	1		P4
RYR1	ENST00000594335.5	c.809G>A	p.Arg270Gln	missense_variant, NMD_transcript_variant	7/49	1
RYR1	ENST00000599547.6	c.7355G>A	p.Arg2452Gln	missense_variant, NMD_transcript_variant	46/80	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251192 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135882

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461334 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 726960

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:4 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2019	- -
not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -

Malignant hyperthermia, susceptibility to, 1 Uncertain:2

Uncertain significance, reviewed by expert panel	curation	ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	Dec 21, 2021	This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions. This sequence variant predicts a substitution of arginine with glutamine at codon 2452 of the RYR1 protein, p.(Arg2452Gln). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000009, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode without a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result, PS4 was not implemented (PMID: PMID:16732084). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score >0.85 (0.928) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1, PP3_Moderate. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 08, 2023	This missense variant replaces arginine with glutamine at codon 2452 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 been reported in an individual with a positive Ca2+ induced Ca2+ release test and with a family history of malignant hyperthermia susceptibility (PMID: 16732084). This variant has been identified in 1/251192 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg2452Trp is known to cause malignant hyperthermia susceptibility (ClinVar variation ID: 65979). Although there is a suspicion for a pathogenic role, the available clinical evidence for this p.Arg2452Trp variant is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia. -

RYR1-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 29, 2023

This missense change has been observed in individual(s) with malignant hyperthermia (PMID: 16917943). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg2452 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10823104, 22030266, 22473935, 23394784, 24433488, 25086907). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 133201). This variant is present in population databases (rs193922815, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 2452 of the RYR1 protein (p.Arg2452Gln). -

RYR1-related myopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Jan 25, 2023

The heterozygous p.Arg2542Gln variant in RYR1 was identified by our study in one individual with congenital myopathy. The p.Arg2542Gln variant in RYR1 has been previously reported in one individual with RYR1-related disease (PMID: 16917943) but has been identified in 0.001% (1/113550) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs193922815). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID:133201) and has been interpreted as pathogenic by CeGaT Center for Human Genetics Tuebingen and as a variant of uncertain significance by the ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel and Invitae. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Multiple variants in the same region as the p.Arg2542Gln variant have been reported in association with disease in the literature, suggesting that this variant is in a hot spot and slightly supports pathogenicity (PMID: 21118704). One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.Arg2452Trp, has been reported in association with disease in ClinVar, slightly supporting that a change at this position may not be tolerated (ClinVar Variation ID: 65979). In summary, the clinical significance of the p.Arg2542Gln variant is uncertain. ACMG/AMP Criteria applied: PM1_Supporting, PM5_Supporting, PP3 (Richards 2015). -

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 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.8	D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.77
MutPred		0.88		Loss of methylation at R2452 (P = 0.0634);Loss of methylation at R2452 (P = 0.0634);
MVP		1.0
MPC		0.40
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.80
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs193922815; hg19: chr19-38991277;