rs146429605

Variant names:

• chr19-38483293-A-G
• rs146429605
• NM_000540.3:c.4711A>G

Your query was ambiguous. Multiple possible variants found:

• chr19-38483293-A-G
• chr19-38483293-A-C
• chr19-38483293-A-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

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 Valine at codon 1571 of the RYR1 protein, p.(Ile1571Val). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0014, this is considered to be more common than expected for a pathogenic variant causing autosomal dominantly inherited MHS, BS1. This variant has been reported in five unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all 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), (PMID:25958340, PMID:20681998, PMID:25658027, PMID:25735680). However, the high MAF in the NFE population in gnomAD precludes the use of PS4. 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 0.56 supports neither a pathogenic nor a benign status for this variant. Based on using Bayes to combine criteria this variant is assessed as Likely Benign, (PMID:29300386). Criteria implemented: BS1.  LINK:https://erepo.genome.network/evrepo/ui/classification/CA024455/MONDO:0007783/012

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0012 (3 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Likely benign reviewed by expert panel P:1 U:16 B:8
• Conservation: PhyloP100: 2.60
• Publications: 18 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), PanelApp Australia, Genomics England PanelApp, Ambry Genetics, ClinGen
• RYR1-related myopathy

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia
• congenital multicore myopathy with external ophthalmoplegia

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• central core myopathy

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), 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: Likely_benign. The variant received -4 ACMG points.

• BS1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000540.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	NM_000540.3	MANE Select	c.4711A>G	p.Ile1571Val	missense	Exon 33 of 106	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.4711A>G	p.Ile1571Val	missense	Exon 33 of 105	NP_001036188.1	P21817-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	ENST00000359596.8	TSL:5 MANE Select	c.4711A>G	p.Ile1571Val	missense	Exon 33 of 106	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.4711A>G	p.Ile1571Val	missense	Exon 33 of 105	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.4711A>G		non_coding_transcript_exon	Exon 33 of 103	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes AF: 0.00109 AC: 166 AN: 152128 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00162

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000895 AC: 150 AN: 167524 AF XY: 0.000934

Gnomad AFR exome AF: 0.000102

Gnomad AMR exome AF: 0.00102

Gnomad ASJ exome AF: 0.000575

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00146

Gnomad OTH exome AF: 0.000642

GnomAD4 exome AF: 0.00121 AC: 1705 AN: 1408196 Hom.: 3 Cov.: 32 AF XY: 0.00125 AC XY: 869 AN XY: 695748

African (AFR) AF: 0.0000929 AC: 3 AN: 32306

American (AMR) AF: 0.00102 AC: 37 AN: 36308

Ashkenazi Jewish (ASJ) AF: 0.000554 AC: 14 AN: 25268

East Asian (EAS) AF: 0.00 AC: 0 AN: 36874

South Asian (SAS) AF: 0.000584 AC: 47 AN: 80466

European-Finnish (FIN) AF: 0.0000207 AC: 1 AN: 48372

Middle Eastern (MID) AF: 0.00176 AC: 10 AN: 5686

European-Non Finnish (NFE) AF: 0.00142 AC: 1540 AN: 1084496

Other (OTH) AF: 0.000907 AC: 53 AN: 58420

GnomAD4 genome AF: 0.00109 AC: 166 AN: 152246 Hom.: 1 Cov.: 31 AF XY: 0.00109 AC XY: 81 AN XY: 74440

African (AFR) AF: 0.0000963 AC: 4 AN: 41548

American (AMR) AF: 0.00268 AC: 41 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00162 AC: 110 AN: 67992

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00138 Hom.: 1

Bravo AF: 0.00105

ESP6500AA AF: 0.000229 AC: 1

ESP6500EA AF: 0.00129 AC: 11

ExAC AF: 0.000603 AC: 71

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	6	2	not provided (8)
-	1	5	Malignant hyperthermia, susceptibility to, 1 (6)
-	2	1	not specified (3)
1	1	-	Central core myopathy (2)
-	2	-	RYR1-related disorder (2)
-	1	-	Anterior segment dysgenesis 7 (1)
-	1	-	Congenital myopathy with fiber type disproportion;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy (1)
-	1	-	RYR1-related myopathy (1)
-	1	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.050
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.016	T
MetaSVM	Uncertain	0.18	D
MutationAssessor	Benign	0.49	N
PhyloP100		2.6
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.27	N
REVEL	Uncertain	0.56
Sift	Benign	0.73	T
Polyphen		0.99	D
Vest4		0.65
MVP		0.94
MPC		0.32
ClinPred		0.022	T
GERP RS		4.0
Varity_R		0.061
gMVP		0.21
Mutation Taster		=41/59	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: rs146429605; hg19: chr19-38973933;