19-38519237-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM5 PP2 PP3_Moderate

The NM_000540.3(RYR1):c.10042C>T(p.Arg3348Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000781 in 1,614,010 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. R3348H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000078 (0 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:12
• Conservation: PhyloP100: 1.73

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 Uncertain_significance. Variant got 5 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-38519238-G-A is described in Lovd as [Pathogenic].
• PP2: Missense variant where missense usually causes diseases, RYR1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.906

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.10042C>T	p.Arg3348Cys	missense_variant	67/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.10042C>T	p.Arg3348Cys	missense_variant	67/106	5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.10042C>T	p.Arg3348Cys	missense_variant	67/105	1		P4
RYR1	ENST00000594335.5	c.*785C>T		3_prime_UTR_variant, NMD_transcript_variant	27/49	1
RYR1	ENST00000599547.6	c.*801C>T		3_prime_UTR_variant, NMD_transcript_variant	66/80	2

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152184 Hom.: 0 Cov.: 31

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: 0.000162

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000638 AC: 16 AN: 250976 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135726

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000780 AC: 114 AN: 1461826 Hom.: 0 Cov.: 32 AF XY: 0.0000853 AC XY: 62 AN XY: 727220

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000908

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152184 Hom.: 0 Cov.: 31 AF XY: 0.0000807 AC XY: 6 AN XY: 74350

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: 0.000162

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000772 Hom.: 0

Bravo AF: 0.0000453

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000741 AC: 9

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:12

Revision: reviewed by expert panel

Submissions by phenotype

Malignant hyperthermia, susceptibility to, 1 Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 01, 2023	This missense variant replaces arginine with cysteine at codon 3348 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). A functional study in patient-derived muscle cells showed cells carrying this variant were more sensitive to caffeine and halothane, but not 4-CmC, than cells carrying wild-type RYR1 (PMID: 22415532). This variant has been reported in two families affected with malignant hyperthermia susceptibility (PMID: 22415532, 30236257). One family also carried a pathogenic variant in the RYR1 gene that could explain the observed phenotype (PMID: 22415532). This variant has been identified in 19/282350 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	The RYR1 c.10042C>T (p.Arg3348Cys) variant has been reported in one study in which it was found in two individuals from the same family (Kaufmann et al. 2012). The index individual was compound heterozygous for the p.Arg3348Cys variant and a second missense variant and was found to be susceptible to malignant hyperthermia based on an in vitro contracture test. In addition, her mother was heterozygous for the p.Arg3348Cys variant and exhibited malignant hyperthermia equivocal to halothane based on an in vitro contracture test. The index individual's sister was heterozygous for the other missense variant and was also susceptible to malignant hyperthermia. In the presence of halothane, cells that carried the p.Arg3348Cys variant were three times more sensitive than control cells, and in cells that carried both variants, the reaction sensitivity was increased even further. The p.Arg3348Cys variant was absent from 105 controls and is reported at a frequency of 0.00014 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the limited evidence, the p.Arg3348Cys variant is classified as a variant of unknown significance but suspicious for pathogenicity for malignant hyperthermia susceptibility. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Uncertain significance, reviewed by expert panel	curation	ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	Apr 06, 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 arginine with cysteine at codon 3348 of the RYR1 protein, p.(Arg3348Cys). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000132, 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 and 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) (PMID:30236257), PS4_Supporting. No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.603 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 13, 2023	This missense variant replaces arginine with cysteine at codon 3348 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). A functional study in patient-derived muscle cells showed cells carrying this variant were more sensitive to caffeine and halothane, but not 4-CmC, than cells carrying wild-type RYR1 (PMID: 22415532). This variant has been reported in two families affected with malignant hyperthermia susceptibility (PMID: 22415532, 30236257). One family also carried a pathogenic variant in the RYR1 gene that could explain the observed phenotype (PMID: 22415532). This variant has been identified in 19/282350 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Oct 28, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 24, 2023	- -

Congenital multicore myopathy with external ophthalmoplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Central core myopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

RYR1-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 01, 2022

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 3348 of the RYR1 protein (p.Arg3348Cys). This variant is present in population databases (rs118204421, gnomAD 0.02%). This missense change has been observed in individual(s) with malignant hyperthermia (PMID: 22415532). ClinVar contains an entry for this variant (Variation ID: 329095). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Congenital myopathy with fiber type disproportion Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Sep 11, 2019

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3,PP5. -

Neuromuscular disease, congenital, with uniform type 1 fiber Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

Feb 11, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Uncertain	0.090
Cadd	Benign	22
Dann	Benign	0.97
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Benign	1.1	L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.8	D;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0030	D;D
Polyphen		1.0	D;D
Vest4		0.77
MVP		0.99
MPC		0.41
ClinPred		0.61	D
GERP RS		3.5
Varity_R		0.32
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs118204421; hg19: chr19-39009877;