rs193922855

Variant names:

• chr19-38565218-C-T
• rs193922855
• NM_000540.3:c.12884C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-38565218-C-T
• chr19-38565218-C-G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BS2_Supporting BS1 BP4 BP2

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 Alanine with Valine at codon 4295 of the RYR1 protein, p.(Ala4295Val). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0019, 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 two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, both 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:30236257). However, the high MAF in the NFE population in gnomAD precludes the use of PS4. This variant has been identified in an individual with a negative IVCT/CHCT result, BS2_Moderate, (PMID:25658027). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. This variant was observed in cis with a variant assessed as pathogenic, p.(Arg2435His), BP2 (PMID:19513315). A REVEL score <0.5 (0.152) supports a benign status for this variant, BP4. Based on using Bayes to combine criteria this variant is assessed as Benign, (PMID:29300386). Criteria implemented: BS1, BS2_Moderate, BP2, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA024018/MONDO:0007783/012

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (6 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Benign reviewed by expert panel U:12 B:6 O:2
• Conservation: PhyloP100: 0.150
• Publications: 8 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: Benign. The variant received -7 ACMG points.

• BP2: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: 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.12884C>T	p.Ala4295Val	missense	Exon 91 of 106	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.12869C>T	p.Ala4290Val	missense	Exon 90 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.12884C>T	p.Ala4295Val	missense	Exon 91 of 106	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.12869C>T	p.Ala4290Val	missense	Exon 90 of 105	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.*3594C>T		non_coding_transcript_exon	Exon 88 of 103	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes AF: 0.00202 AC: 295 AN: 145848 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00136

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000612

Gnomad ASJ AF: 0.000295

Gnomad EAS AF: 0.000981

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00357

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00295

Gnomad OTH AF: 0.000496

GnomAD2 exomes AF: 0.00 AC: 0 AN: 272 AF XY: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00339 AC: 2869 AN: 845864 Hom.: 6 Cov.: 30 AF XY: 0.00342 AC XY: 1342 AN XY: 392204

African (AFR) AF: 0.000628 AC: 10 AN: 15932

American (AMR) AF: 0.00 AC: 0 AN: 1458

Ashkenazi Jewish (ASJ) AF: 0.000556 AC: 3 AN: 5394

East Asian (EAS) AF: 0.00175 AC: 7 AN: 4000

South Asian (SAS) AF: 0.000230 AC: 4 AN: 17408

European-Finnish (FIN) AF: 0.00699 AC: 11 AN: 1574

Middle Eastern (MID) AF: 0.000602 AC: 1 AN: 1662

European-Non Finnish (NFE) AF: 0.00361 AC: 2784 AN: 770438

Other (OTH) AF: 0.00175 AC: 49 AN: 27998

GnomAD4 genome AF: 0.00202 AC: 295 AN: 145958 Hom.: 0 Cov.: 32 AF XY: 0.00189 AC XY: 134 AN XY: 71008

African (AFR) AF: 0.00136 AC: 55 AN: 40544

American (AMR) AF: 0.000611 AC: 9 AN: 14722

Ashkenazi Jewish (ASJ) AF: 0.000295 AC: 1 AN: 3386

East Asian (EAS) AF: 0.000984 AC: 5 AN: 5080

South Asian (SAS) AF: 0.00 AC: 0 AN: 4796

European-Finnish (FIN) AF: 0.00357 AC: 30 AN: 8398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.00295 AC: 194 AN: 65800

Other (OTH) AF: 0.000490 AC: 1 AN: 2040

Alfa AF: 0.000271 Hom.: 0

Bravo AF: 0.00161

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	8	2	not provided (11)
-	1	1	Malignant hyperthermia, susceptibility to, 1 (2)
-	1	-	Central core myopathy (1)
-	1	-	Congenital multicore myopathy with external ophthalmoplegia (1)
-	-	1	Inborn genetic diseases (1)
-	1	-	King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy (1)
-	-	1	not specified (1)
-	-	1	RYR1-related disorder (1)
-	-	-	Multiminicore myopathy;C0546264:Congenital myopathy with fiber type disproportion;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy;CN221567:Myopathy, RYR1-associated (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	13
DANN	Benign	0.95
DEOGEN2	Benign	0.32	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.50	T
M_CAP	Pathogenic	0.99	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.15
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	0.10	N
REVEL	Benign	0.15
Sift	Benign	0.54	T
Polyphen		0.0	B
Vest4		0.092
MVP		0.77
MPC		0.73
ClinPred		0.055	T
GERP RS		0.013
PromoterAI		-0.037	Neutral
Varity_R		0.026
gMVP		0.33
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

dbSNP: rs193922855; hg19: chr19-39055858;