19-38528963-CAGGAGGAGG-CAGGAGG

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP3 BP6

The NM_000540.3(RYR1):c.11061_11063del(p.Glu3689del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.00068 in 1,581,278 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00062 (3 hom.)
• Consequence: RYR1 NM_000540.3 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:3
• Conservation: PhyloP100: 4.54

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 Likely_benign. Variant got -2 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_000540.3
• BP6: Variant 19-38528963-CAGG-C is Benign according to our data. Variant chr19-38528963-CAGG-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 218465.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=4, Benign=2}. Variant chr19-38528963-CAGG-C is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.11061_11063del	p.Glu3689del	inframe_deletion	76/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.11061_11063del	p.Glu3689del	inframe_deletion	76/106	5	NM_000540.3	A2

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 185 AN: 151988 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00249

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000177

Gnomad OTH AF: 0.000957

GnomAD4 exome AF: 0.000623 AC: 891 AN: 1429174 Hom.: 3 AF XY: 0.000607 AC XY: 431 AN XY: 710134

Gnomad4 AFR exome AF: 0.00314

Gnomad4 AMR exome AF: 0.000605

Gnomad4 ASJ exome AF: 0.0188

Gnomad4 EAS exome AF: 0.0000515

Gnomad4 SAS exome AF: 0.000180

Gnomad4 FIN exome AF: 0.0000962

Gnomad4 NFE exome AF: 0.000148

Gnomad4 OTH exome AF: 0.00173

GnomAD4 genome AF: 0.00122 AC: 185 AN: 152104 Hom.: 0 Cov.: 32 AF XY: 0.00116 AC XY: 86 AN XY: 74356

Gnomad4 AFR AF: 0.00248

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.0187

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000177

Gnomad4 OTH AF: 0.000948

Bravo AF: 0.00133

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

RYR1-related disorder Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 29, 2024	The RYR1 c.11061_11063delGGA variant is predicted to result in an in-frame deletion (p.Glu3689del). This variant has been reported in two individuals with no history of malignant hyperthermia, heat illness, or myopathy (Table S3 - Gonsalves et al. 2013. PubMed ID: 24195946). This variant was also reported in an individual with hypertrophied muscles and persistently elevated serum creatine kinase (Vedanarayanan. American Academy of Neurology 2013 Annual Meeting; https://www.aan.com/MSA/Public/Events/Details/2786). This variant is reported in 1.8% of alleles in individuals of Ashkenazi Jewish descent in gnomAD; however, quality metrics at this site indicate this may not be a reliable estimate of the population frequency. At PreventionGenetics, we have observed this variant in the heterozygous state in ~90 individuals indicating it is likely too common to be a primary cause of an autosomal dominant disorder. Although we suspect this variant is benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Malignant hyperthermia, susceptibility to, 1 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 01, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 28, 2019	- -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2023	Identified as a heterozygous variant in a cohort of African American men with muscle cramps and pain with exertion (Vedanarayanan and Sinclair, 2013); In silico analysis supports a deleterious effect on protein structure/function -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	RYR1: BS1, BS2 -

Malignant hypothermia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Apr 17, 2015

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs760784102; hg19: chr19-39019603;