19-38565283-GTGCGGCGGC-GTGCGGCGGCTGCGGCGGC

Variant names:

Variant summary

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

The NM_000540.3(RYR1):c.12960_12968dupGCGGCGGCT(p.Leu4323_Thr4324insArgArgLeu) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000428 in 1,005,090 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L4323L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000082 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

RYR1
NM_000540.3 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7O:1

Conservation

PhyloP100: 1.66

Publications

1 publications found

Variant links:

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

RYR1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_000540.3.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3 link	c.12960_12968dupGCGGCGGCT	p.Leu4323_Thr4324insArgArgLeu	disruptive_inframe_insertion	Exon 91 of 106	ENST00000359596.8	NP_000531.2	P21817-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8 link	c.12960_12968dupGCGGCGGCT	p.Leu4323_Thr4324insArgArgLeu	disruptive_inframe_insertion	Exon 91 of 106	5	NM_000540.3	ENSP00000352608.2		P21817-1

Frequencies

GnomAD3 genomes

AF:

0.0000818

AC:

AN:

146752

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000489

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000271

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000390

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000606

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000361

AC:

AN:

858338

Hom.:

Cov.:

AF XY:

0.0000226

AC XY:

AN XY:

398990

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

16264

American (AMR)

AF:

0.00

AC:

AN:

1922

Ashkenazi Jewish (ASJ)

AF:

0.000176

AC:

AN:

5692

East Asian (EAS)

AF:

0.00

AC:

AN:

4512

South Asian (SAS)

AF:

0.0000570

AC:

AN:

17536

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3196

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1724

European-Non Finnish (NFE)

AF:

0.0000334

AC:

AN:

778712

Other (OTH)

AF:

0.000104

AC:

AN:

28780

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000818

AC:

AN:

146752

Hom.:

Cov.:

AF XY:

0.0000840

AC XY:

AN XY:

71388

show subpopulations

African (AFR)

AF:

0.0000489

AC:

AN:

40910

American (AMR)

AF:

0.000271

AC:

AN:

14768

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3392

East Asian (EAS)

AF:

0.000390

AC:

AN:

5134

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8512

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.0000606

AC:

AN:

65964

Other (OTH)

AF:

0.00

AC:

AN:

2022

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.408

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:5Other:1

RYR1 database

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Mar 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 15, 2022

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The RYR1 c.12960_12968dup (p.Arg4321_Leu4323dup) variant results in a duplication of three amino acids in a non-repetitive region, arginine, arginine and leucine, at amino acid positions 4321, 4322 and 4323, respectively. This is an inframe event and is therefore predicted to preserve the reading frame. This variant is also referred to as c.12959_12967dup (p.Arg4320_Leu4322dup). The p.Arg4321_Leu4323dup has been reported in a heterozygous state in two individuals, an adult with elevated CK and an abnormal calcium-induced calcium release (CICR) test, and a child who expired following prolonged exposure to high temperature. However, neither were definitively diagnosed with malignant hyperthermia susceptibility at the time of reporting (PMID: 16732084; PMID: 19223216). The highest frequency of this allele in the Genome Aggregation Database is 0.000390 in the East Asian population (version 3.1.2). The p.Arg4321_Leu4323dup variant is in the CaM binding domain 3 (CaMBD3) of the RyR1 protein and isothermal titration calorimetry demonstrates that the variant results in altered binding between RyR1 and CaM, however the clinical implications of this finding are unclear (PMID: 24447242). Based on the available evidence, the c.12960_12968dup variant is classified as a variant of uncertain significance for malignant hyperthermia susceptibility. -

Aug 28, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 22, 2020

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 16, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported (as c.12959_12967dup) in an individual with elevated creatine kinase levels and malignant hyperthermia susceptibility (PMID: 16732084); Identified with a second variant in an individual that died after being exposed to extreme heat for a significant amount of time (PMID: 19223216); In-frame insertion of 3 amino acids in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23476141, 19223216, 16732084) -

RYR1-related disorder

Uncertain:1

Nov 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.12960_12968dup, results in the insertion of 3 amino acid(s) of the RYR1 protein (p.Arg4321_Leu4323dup), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been observed in individual(s) with increased serum creatine kinase and malignant hyperthermia susceptibility (PMID: 16732084). This variant is also known as c.12959_12967dup, L4320_R4322dup, duplication of L4319 to R4321. ClinVar contains an entry for this variant (Variation ID: 133044). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects RYR1 function (PMID: 24447242). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

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

Uncertain:1

Aug 23, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.7

Mutation Taster

=36/64

disease causing

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over