NM_000540.3:c.12960_12968delGCGGCGGCT

Variant names:

• chr19-38565283-GTGCGGCGGC-G
• rs193922846
• NM_000540.3:c.12960_12968delGCGGCGGCT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The NM_000540.3(RYR1):​c.12960_12968delGCGGCGGCT​(p.Arg4321_Leu4323del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.000103 in 1,005,090 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000095 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: RYR1 NM_000540.3 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 4.74
• Publications: 1 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 2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000540.3.

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.12960_12968delGCGGCGGCT	p.Arg4321_Leu4323del	disruptive_inframe_deletion	Exon 91 of 106	NP_000531.2
	RYR1	NM_001042723.2		c.12945_12953delGCGGCGGCT	p.Arg4316_Leu4318del	disruptive_inframe_deletion	Exon 90 of 105	NP_001036188.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	ENST00000359596.8	TSL:5 MANE Select	c.12960_12968delGCGGCGGCT	p.Arg4321_Leu4323del	disruptive_inframe_deletion	Exon 91 of 106	ENSP00000352608.2
	RYR1	ENST00000355481.8	TSL:1	c.12945_12953delGCGGCGGCT	p.Arg4316_Leu4318del	disruptive_inframe_deletion	Exon 90 of 105	ENSP00000347667.3
	RYR1	ENST00000594335.6	TSL:1	n.*3670_*3678delGCGGCGGCT		non_coding_transcript_exon	Exon 88 of 103	ENSP00000470927.2

Frequencies

GnomAD3 genomes AF: 0.0000954 AC: 14 AN: 146752 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000978

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000136

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000105 AC: 90 AN: 858338 Hom.: 0 AF XY: 0.0000727 AC XY: 29 AN XY: 398990

African (AFR) AF: 0.000123 AC: 2 AN: 16264

American (AMR) AF: 0.00 AC: 0 AN: 1922

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5692

East Asian (EAS) AF: 0.000887 AC: 4 AN: 4512

South Asian (SAS) AF: 0.00 AC: 0 AN: 17536

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3196

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1724

European-Non Finnish (NFE) AF: 0.000105 AC: 82 AN: 778712

Other (OTH) AF: 0.0000695 AC: 2 AN: 28780

GnomAD4 genome AF: 0.0000954 AC: 14 AN: 146752 Hom.: 0 Cov.: 31 AF XY: 0.0000420 AC XY: 3 AN XY: 71388

African (AFR) AF: 0.0000978 AC: 4 AN: 40910

American (AMR) AF: 0.00 AC: 0 AN: 14768

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3392

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5134

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8512

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.000136 AC: 9 AN: 65964

Other (OTH) AF: 0.00 AC: 0 AN: 2022

Alfa AF: 0.000216 Hom.: 0

Bravo AF: 0.0000756

Asia WGS AF: 0.000365 AC: 1 AN: 2750

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	1	-	Congenital myopathy with fiber type disproportion;C1840365:King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy (1)
-	-	1	Intellectual disability (1)
-	1	-	RYR1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.7
Mutation Taster		=72/128	disease causing

Splicing

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

Other links and lift over

dbSNP: rs193922846; hg19: chr19-39055923;