19-38565283-GTGCGGCGGC-GTGCGGCGGCTGCGGCGGC

Variant names:

• chr19-38565283-G-GTGCGGCGGC
• rs193922846
• NM_000540.3:c.12960_12968dupGCGGCGGCT

Variant summary

Our verdict is Uncertain significance. Variant got 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.000082 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: RYR1 NM_000540.3 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7 O:1
• Conservation: PhyloP100: 1.66

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 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	c.12960_12968dupGCGGCGGCT	p.Leu4323_Thr4324insArgArgLeu	disruptive_inframe_insertion	Exon 91 of 106	ENST00000359596.8	NP_000531.2

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0000818 AC: 12 AN: 146752 Hom.: 0 Cov.: 32

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: 31 AN: 858338 Hom.: 0 Cov.: 30 AF XY: 0.0000226 AC XY: 9 AN XY: 398990

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000176

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000570

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000334

Gnomad4 OTH exome AF: 0.000104

GnomAD4 genome AF: 0.0000818 AC: 12 AN: 146752 Hom.: 0 Cov.: 32 AF XY: 0.0000840 AC XY: 6 AN XY: 71388

Gnomad4 AFR AF: 0.0000489

Gnomad4 AMR AF: 0.000271

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000390

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000606

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:5 Other:1

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. -

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 database

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Aug 28, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2017

CeGaT Center for Human Genetics Tuebingen

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

- -

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs193922846; hg19: chr19-39055923;