rs118192126

Variant names:

• chr19-38519295-A-G
• rs118192126
• NM_000540.3:c.10100A>G

Your query was ambiguous. Multiple possible variants found:

• chr19-38519295-A-G
• chr19-38519295-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2_Supporting PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The variant NM_000540.3:c.10100A>G in RYR1 is a missense variant predicted to cause substitution of lysine by arginine at amino acid 3367 (p.Lys3367Arg). The variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.632, which is neither above nor below the thresholds predicting a damaging or benign impact on RYR1 function. This variant has been reported in one proband with central core disease (PS4_Supporting; PMID:16621918). In summary, this variant meets the criteria to be classified as uncertain significance for AD RYR1-related myopathy. ACMG/AMP criteria met, as specified by the Congenital Myopathies VCEP (Specification Version 1.0.0): PM2_Supporting, PS4_Supporting (ClinGen Congenital Myopathies VCEP specifications version 2.0.0; 11/18/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA023815/MONDO:0100150/150

• Frequency: Genomes: not found (cov: 31)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:2 O:1
• Conservation: PhyloP100: 7.51
• Publications: 2 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: Uncertain_significance. The variant received 2 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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.10100A>G	p.Lys3367Arg	missense	Exon 67 of 106	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.10100A>G	p.Lys3367Arg	missense	Exon 67 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.10100A>G	p.Lys3367Arg	missense	Exon 67 of 106	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.10100A>G	p.Lys3367Arg	missense	Exon 67 of 105	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.*843A>G		non_coding_transcript_exon	Exon 66 of 103	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Central core myopathy (1)
-	1	-	Malignant hyperthermia, susceptibility to, 1 (1)
-	1	-	RYR1-related myopathy (1)
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	24
DANN	Benign	0.82
DEOGEN2	Uncertain	0.67	D
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.060
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Benign	2.0	M
PhyloP100		7.5
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.63
Sift	Benign	0.10	T
Polyphen		0.041	B
Vest4		0.70
MutPred		0.69		Loss of methylation at K3367 (P = 0.0266)
MVP		1.0
MPC		0.26
ClinPred		0.74	D
GERP RS		3.5
Varity_R		0.27
gMVP		0.30
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.30		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs118192126; hg19: chr19-39009935;