rs375626634

Positions:

• chr19-38517431-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

This summary comes from the ClinGen Evidence Repository: 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 isoleucine with threonine at codon 3253 of the RYR1 protein, p.(Ile3253Thr). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.000201, a frequency consistent with pathogenicity for MHS. This variant has not to our knowledge been reported in any individuals with a personal history of an MH episode or a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result. 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 0.845 supports neither a pathogenic nor a benign status for this variant. This variant has been classified a Variant of Unknown Significance. Criteria implemented: none. LINK:https://erepo.genome.network/evrepo/ui/classification/CA025003/MONDO:0007783/012

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:10 B:2
• Conservation: PhyloP100: 7.97

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 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.9758T>C	p.Ile3253Thr	missense_variant	66/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.9758T>C	p.Ile3253Thr	missense_variant	66/106	5	NM_000540.3	ENSP00000352608	A2
RYR1	ENST00000355481.8	c.9758T>C	p.Ile3253Thr	missense_variant	66/105	1		ENSP00000347667	P4
RYR1	ENST00000594335.5	c.*501T>C		3_prime_UTR_variant, NMD_transcript_variant	26/49	1		ENSP00000470927
RYR1	ENST00000599547.6	c.*517T>C		3_prime_UTR_variant, NMD_transcript_variant	65/80	2		ENSP00000471601

Frequencies

GnomAD3 genomes AF: 0.0000527 AC: 8 AN: 151924 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000193

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000360 AC: 9 AN: 249686 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135182

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1461872 Hom.: 0 Cov.: 34 AF XY: 0.0000193 AC XY: 14 AN XY: 727236

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.0000993

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152042 Hom.: 0 Cov.: 31 AF XY: 0.0000403 AC XY: 3 AN XY: 74350

Gnomad4 AFR AF: 0.000193

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: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000324 Hom.: 0

Bravo AF: 0.0000680

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:10 Benign:2

Revision: reviewed by expert panel

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 11, 2023	This missense variant replaces isoleucine with threonine at codon 3253 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 individuals affected with malignant hyperthermia susceptibility (PMID: 23035052, 25658027, 26994242). This variant has been identified in 10/280974 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. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
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 isoleucine with threonine at codon 3253 of the RYR1 protein, p.(Ile3253Thr). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.000201, a frequency consistent with pathogenicity for MHS. This variant has not to our knowledge been reported in any individuals with a personal history of an MH episode or a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result. 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 0.845 supports neither a pathogenic nor a benign status for this variant. This variant has been classified a Variant of Unknown Significance. Criteria implemented: none. -

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 29, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 15, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 03, 2023	Reported previously as a variant of uncertain significance in a patient with a clinical diagnosis of congenital myopathy; however, no further clinical or segregation information was provided (Galleni Leo et al., 2020); Identified in individuals with heat stroke (Schiermann et al., 2013) and malignant hyperthermia (Roux-Buisson et al., 2016), however was reported to not segregate with malignant hyperthermia in the family (Roux-Buisson et al., 2016); Reported in one affected individual and described as a likely pathogenic variant in association with exertional heat illness, myalgia and hyperCKemia (Gardner et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28326467, 23035052, 26994242, 25637381, 30611313, 32054689, 23826317, 33458582) -

Central core myopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant c.9758T>C (p.Ile3253Thr) in RYR1 has been submitted to ClinVar as a Variant of Uncertain Significance (VUS), but no details are available for independent assessment. It has not been reported in affected individuals. This p.Ile3253Thr variant has allele frequency 0.0036% in the gnomad and novel (not in any individuals) in 1000 genome database. The amino acid Ile at position 3253 is changed to a Thr changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Ile3253Thr in RYR1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance (VUS). -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 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 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 30, 2023

ClinVar contains an entry for this variant (Variation ID: 159865). 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 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 missense change has been observed in individual(s) with clinical features of autosomal dominant RYR1-related conditions (PMID: 23035052, 32054689, 33458582). This variant has been reported in individual(s) with autosomal recessive congenital myopathy (PMID: 23826317); however, the role of the variant in this condition is currently unclear. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 3253 of the RYR1 protein (p.Ile3253Thr). -

Congenital multicore myopathy with external ophthalmoplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 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. -

Congenital myopathy Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Pathogenic	0.16
CADD	Benign	23
DANN	Benign	0.61
DEOGEN2	Uncertain	0.79	.;D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Uncertain	2.7	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-4.2	D;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0010	D;D
Polyphen		0.99	D;D
Vest4		0.82
MVP		0.96
MPC		0.40
ClinPred		0.32	T
GERP RS		4.2
Varity_R		0.62
gMVP		0.74

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: rs375626634; hg19: chr19-39008071;