rs193922797

chr19-38496901-G-Achr19-38496901-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PP2 PP5_Very_Strong

The NM_000540.3(RYR1):c.6838G>A(p.Val2280Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000614 in 1,613,396 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2280F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000064 (0 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:5 U:6 O:1
• Conservation: PhyloP100: 7.53

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 11 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000540.3
• PP2: Missense variant where missense usually causes diseases, RYR1
• PP5: Variant 19-38496901-G-A is Pathogenic according to our data. Variant chr19-38496901-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 133172.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-38496901-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.6838G>A	p.Val2280Ile	missense_variant	42/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.6838G>A	p.Val2280Ile	missense_variant	42/106	5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.6838G>A	p.Val2280Ile	missense_variant	42/105	1		P4
RYR1	ENST00000594335.5	c.292G>A	p.Val98Ile	missense_variant, NMD_transcript_variant	3/49	1
RYR1	ENST00000599547.6	c.6838G>A	p.Val2280Ile	missense_variant, NMD_transcript_variant	42/80	2

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000240 AC: 6 AN: 250004 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135562

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.0000354

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000636 AC: 93 AN: 1461194 Hom.: 0 Cov.: 32 AF XY: 0.0000647 AC XY: 47 AN XY: 726898

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000758

Gnomad4 NFE exome AF: 0.0000728

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74364

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000502 Hom.: 0

Bravo AF: 0.0000604

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5 Uncertain:6 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 19, 2023	This missense variant replaces valine with isoleucine at codon 2280 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). Although functional studies have not been reported for this variant, it occurs in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to malignant hyperthermia susceptibility (PMID: 21118704). This variant has been reported in at least 4 families or individuals affected with malignant hyperthermia susceptibility (PMID: 16835904, 30236257, 30864471, 36208971, 36208971, ClinVar: SCV001810122.1). It has been shown that this variant segregates with malignant hyperthermia susceptibility in 8 individuals of 1 family (PMID: 36208971). This variant has been identified in 6/250004 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Likely pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Jul 17, 2014	This test identified one heterozygous variant (c.6838G>A;p.Val2280Ile) in the RYR1 gene (see Table IIIA). Variants in this gene have been associated with increased risk of malignant hyperthermia (autosomal dominant) and different types of congenital myopathies - central core disease (autosomal dominant or autosomal recessive), multiminicore disease (autosomal recessive), congenital fiber type disproportion (autosomal dominant or autosomal recessive). The RYR1 gene encodes for calcium channels that play a critical role in the movement of skeletal muscles. Risk for malignant hyperthermia is predominantly associated with the use of general anesthesia with specific anesthetics, which can trigger an episode (hypermetabolism, rhabdomyolysis, hyperkalaemia, cardiac arrhythmia). A very small number of individuals with malignant hyperthermia susceptibility appear to be at risk for heat stroke or exercise-induced rhabdomyolysis,). Malignant hyperthermia has been reported to occur in individuals without anesthetic exposure. If an episode is untreated, it can be life threatening. Alternative anesthetic treatments are available for known individuals susceptible to malignant hyperthermia. This variant has been reported in a family susceptible to malignant hyperthermia based on biochemical testing (Galli et al 2002,PMID: 12208234; Galli et al. 2006, PMID: 16835904), and computational evidence is also suggestive of this variant being a pathogenic variant. -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	May 20, 2023	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 valine with isoleucine at codon 2280 of the RYR1 protein, p.(Val2280Ile). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000035, a frequency consistent with pathogenicity for MHS. This variant has been reported in three unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, two of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID:30864471, PMID:30236257; MHIU Toronto - MH proband CGS 45). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:36208971). 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 of 0.641 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Likely Pathogenic. Criteria implemented: PS3_Moderate, PS4_Moderate, PM1. -

not provided Uncertain:3 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 14, 2022	- -
not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 03, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Sep 27, 2017	- -

RYR1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 28, 2023

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 2280 of the RYR1 protein (p.Val2280Ile). This variant is present in population databases (rs193922797, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of autosomal dominant RYR1-related conditions and/or malignant hyperthermia susceptibility (PMID: 12208234, 30236257, 30788618, 31559918, 36208971; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 133172). 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) has been performed at Invitae 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. Experimental studies have shown that this missense change affects RYR1 function (PMID: 36208971). For these reasons, this variant has been classified as Pathogenic. -

Malignant hyperthermia of anesthesia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 25, 2023

Variant summary: RYR1 c.6838G>A (p.Val2280Ile) results in a conservative amino acid change located in the RIH domain (IPR000699) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 250004 control chromosomes. c.6838G>A has been reported in the literature in multiple individuals affected with Malignant Hyperthermia Susceptibility supported by a diagnostic in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (example, Galli_2002, Scalco_2016, Oberg_2016, Knulman_2019, Hudig_2019, Sadhasivam_2019, White_2022). Of these, in one report of families with this variant, eight transmissions of the variant allele and 2 transmissions of the reference allele to affected Malignant Hyperthermia Susceptible individuals was reported (White_2022). This study included this variant among RYR-1 disease causing variants for diagnostic use managed by the European Malignant Hyperthermia Group. These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence evaluating an impact on protein function, demonstrating hypersensitivity to an RyR1 agonist in calcium release assays (White_2022). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters to include the ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, reported the variant with conflicting assessments (VUS, n=6; LP, n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 02, 2017

- -

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

Oct 21, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.24
Cadd	Uncertain	25
Dann	Uncertain	0.98
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Benign	0.085	D
MetaRNN	Uncertain	0.55	D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	0.95	D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.69	N;N
REVEL	Uncertain	0.64
Sift	Uncertain	0.020	D;D
Polyphen		0.94	P;P
Vest4		0.58
MVP		1.0
MPC		0.26
ClinPred		0.41	T
GERP RS		5.0
Varity_R		0.12
gMVP		0.42

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: rs193922797; hg19: chr19-38987541;