chr19-38565182-A-T

Variant names:

• chr19-38565182-A-T
• rs193922853
• NM_000540.3:c.12848A>T

Variant summary

Our verdict is Uncertain significance. The variant received 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 glutamic acid with valine at codon 4283 of the RYR1 protein, p.(Glu4283Val). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in one individual with a personal or family history of a malignant hyperthermia reaction, a second variant of uncertain significance, p.(Val218Ile), was also identified. This individual did not have an in vitro contracture test (IVCT) or a caffeine halothane contracture test (CHCT) result, PS4 was not implemented (PMID:16732084). 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 0.561 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: none. LINK:https://erepo.genome.network/evrepo/ui/classification/CA024011/MONDO:0018493/012

• Frequency:
  • Genomes: 𝑓 0.0000069 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000081 (0 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:1 O:1
• Conservation: PhyloP100: 1.98
• Publications: 0 publications found

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]

RYR1 Gene-Disease associations (from GenCC):

• malignant hyperthermia, susceptibility to, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, Ambry Genetics
• congenital multicore myopathy with external ophthalmoplegia

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• RYR1-related myopathy

  Inheritance: AR, AD Classification: DEFINITIVE Submitted by: ClinGen
• central core myopathy

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• King-Denborough syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• malignant hyperthermia of anesthesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive centronuclear myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• benign Samaritan congenital myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital myopathy with myasthenic-like onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• lethal multiple pterygium syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3	c.12848A>T	p.Glu4283Val	missense_variant	Exon 91 of 106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.12848A>T	p.Glu4283Val	missense_variant	Exon 91 of 106	5	NM_000540.3	ENSP00000352608.2

Frequencies

GnomAD3 genomes AF: 0.00000685 AC: 1 AN: 145888 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000199

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

GnomAD4 exome AF: 0.00000809 AC: 8 AN: 989056 Hom.: 0 Cov.: 30 AF XY: 0.00000643 AC XY: 3 AN XY: 466554

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 18720

American (AMR) AF: 0.00 AC: 0 AN: 5594

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10432

East Asian (EAS) AF: 0.000446 AC: 8 AN: 17922

South Asian (SAS) AF: 0.00 AC: 0 AN: 19714

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 15664

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2418

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 861806

Other (OTH) AF: 0.00 AC: 0 AN: 36786

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000316713), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000685 AC: 1 AN: 145888 Hom.: 0 Cov.: 32 AF XY: 0.0000141 AC XY: 1 AN XY: 71052

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 39746

American (AMR) AF: 0.00 AC: 0 AN: 14776

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3412

East Asian (EAS) AF: 0.000199 AC: 1 AN: 5024

South Asian (SAS) AF: 0.00 AC: 0 AN: 4778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8722

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 304

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66210

Other (OTH) AF: 0.00 AC: 0 AN: 2010

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Malignant hyperthermia of anesthesia Uncertain:1

Apr 06, 2023

ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

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 glutamic acid with valine at codon 4283 of the RYR1 protein, p.(Glu4283Val). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in one individual with a personal or family history of a malignant hyperthermia reaction, a second variant of uncertain significance, p.(Val218Ile), was also identified. This individual did not have an in vitro contracture test (IVCT) or a caffeine halothane contracture test (CHCT) result, PS4 was not implemented (PMID: 16732084). 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 0.561 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: none. -

not provided Other:1

-

RYR1 database

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	18
DANN	Benign	0.81
DEOGEN2	Uncertain	0.59	.;D
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.43	T;T
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Uncertain	0.094	D
MutationAssessor	Benign	0.90	.;L
PhyloP100		2.0
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.7	N;N
REVEL	Uncertain	0.56
Sift	Benign	0.14	T;T
Polyphen		0.0	B;B
Vest4		0.41
MutPred		0.70		.;Gain of MoRF binding (P = 0.0617);
MVP		0.95
MPC		0.84
ClinPred		0.16	T
GERP RS		0.69
PromoterAI		0.014	Neutral
Varity_R		0.081
gMVP		0.53
Mutation Taster		=13/87	disease causing

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

Other links and lift over

dbSNP: rs193922853; hg19: chr19-39055822;