chr19-38580440-G-A

Variant names:

• chr19-38580440-G-A
• rs63749869
• NM_000540.3:c.14582G>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PP1 PP3 PM2_Supporting PS2 PS4 PS3_Supporting PM5

This summary comes from the ClinGen Evidence Repository: The NM_000540.3:c.14582G>A variant in RYR1 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 4861 (p.Arg4861His). The highest population minor allele frequency in gnomAD v4.1 is 0.0000008475 (1/1180004 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Congenital Myopathies VCEP threshold (absent with 1 allele allowed) for PM2_Supporting, meeting this criterion (PM2_Supporting). The REVEL computational prediction analysis tool gives a score of 0.912, which is above the threshold necessary to apply PP3. Four different missense variants, c.14581C>A (p.Arg4861Ser), c.14581C>G (p.Arg4861Gly), c.14581C>T (p.Arg4861Cys), c.14582G>C (p.Arg4861Pro) (ClinVar IDs: 2027376, 943431, 65986, 1066439), in the same codon have been classified as pathogenic/likely pathogenic for RYR1-related myopathy (PM5). This variant has been reported in at least five probands with RYR1-related myopathy which meets the criteria for PS4, two of which were confirmed to be de novo occurrences meeting PS2 (PMIDs:11709545, 35428369, 35081925). The variant has also been reported to segregate in one affected sibling from a family (PP1, PMID:11709545). Calcium homeostasis analysis of immortalized B-lymphocytes from patients showed significantly smaller thapsigargin-sensitive intracellular calcium stores, compared to lymphoblasts from control individuals, indicating that this variant may impact protein function (PS3_Supporting, PMID:11741831). In summary, the variant meets the criteria to be classified as pathogenic for autosomal dominant RYR1-related myopathy. ACMG/AMP criteria met, as specified by the ClinGen Congenital Myopathies VCEP: PS4, PS2, PS3_Supporting, PM5, PM2_Supporting, PP1, PP3 (ClinGen Congenital Myopathies VCEP specifications version 2; 8/27/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA024187/MONDO:0100150/150

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity; drug response reviewed by expert panel P:13 U:1 O:8
• Conservation: PhyloP100: 9.95
• Publications: 32 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: Pathogenic. The variant received 14 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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.14582G>A	p.Arg4861His	missense	Exon 101 of 106	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.14567G>A	p.Arg4856His	missense	Exon 100 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.14582G>A	p.Arg4861His	missense	Exon 101 of 106	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.14567G>A	p.Arg4856His	missense	Exon 100 of 105	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.*5292G>A		non_coding_transcript_exon	Exon 98 of 103	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461872 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity; drug response

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
6	-	-	not provided (7)
3	-	-	Central core myopathy (3)
1	1	-	Malignant hyperthermia, susceptibility to, 1 (2)
1	-	-	Malignant hyperthermia of anesthesia (1)
1	-	-	RYR1-related disorder (1)
1	-	-	RYR1-related myopathy (1)
-	-	-	desflurane response - Toxicity (1)
-	-	-	enflurane response - Toxicity (1)
-	-	-	halothane response - Toxicity (1)
-	-	-	isoflurane response - Toxicity (1)
-	-	-	methoxyflurane response - Toxicity (1)
-	-	-	sevoflurane response - Toxicity (1)
-	-	-	succinylcholine response - Toxicity (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		10
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-4.3	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.80
MutPred		0.87		Loss of stability (P = 0.0924)
MVP		1.0
MPC		0.71
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.87
gMVP		0.97
Mutation Taster		=1/99	disease causing

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: rs63749869; hg19: chr19-39071080;