rs201584482

Positions:

• chr19-38499937-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP2

The NM_000540.3(RYR1):​c.7244G>A​(p.Arg2415Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000684 in 1,607,722 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 0.000034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000072 (0 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1 O:1
• Conservation: PhyloP100: 1.94

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 1 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RYR1. . Gene score misZ 1.918 (greater than the threshold 3.09). Trascript score misZ 3.9788 (greater than threshold 3.09). GenCC has associacion of gene with King-Denborough syndrome, congenital multicore myopathy with external ophthalmoplegia, autosomal recessive centronuclear myopathy, RYR1-related myopathy, lethal multiple pterygium syndrome, malignant hyperthermia of anesthesia, benign Samaritan congenital myopathy, malignant hyperthermia, susceptibility to, 1, congenital myopathy with myasthenic-like onset, central core myopathy.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.7244G>A	p.Arg2415Gln	missense_variant	45/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.7244G>A	p.Arg2415Gln	missense_variant	45/106	5	NM_000540.3	ENSP00000352608.2
RYR1	ENST00000355481.8	c.7244G>A	p.Arg2415Gln	missense_variant	45/105	1		ENSP00000347667.3
RYR1	ENST00000594335.5	n.695G>A		non_coding_transcript_exon_variant	6/49	1		ENSP00000470927.2
RYR1	ENST00000599547.6	n.7244G>A		non_coding_transcript_exon_variant	45/80	2		ENSP00000471601.2

Frequencies

GnomAD3 genomes AF: 0.0000335 AC: 5 AN: 149118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000245

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000594

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000915 AC: 23 AN: 251382 Hom.: 0 AF XY: 0.0000883 AC XY: 12 AN XY: 135890

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000720 AC: 105 AN: 1458604 Hom.: 0 Cov.: 37 AF XY: 0.0000717 AC XY: 52 AN XY: 725658

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000506

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000379

Gnomad4 NFE exome AF: 0.0000856

Gnomad4 OTH exome AF: 0.0000665

GnomAD4 genome AF: 0.0000335 AC: 5 AN: 149118 Hom.: 0 Cov.: 32 AF XY: 0.0000412 AC XY: 3 AN XY: 72774

Gnomad4 AFR AF: 0.0000245

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000594

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000902 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 20, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	RYR1: PM2 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 19, 2024	Reported previously as a heterozygous variant of uncertain significance in a patient with congenital fiber-type disproportion (PMID: 27854218); Reported previously as a heterozygous variant in a patient with aneurysmal subarachnoid hemorrhage without symptomatic vasospasm (PMID: 21503806); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27314601, 28087430, 12668474, 27854218, 21503806) -

RYR1-related disorder Benign:1 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 13, 2023	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Uncertain significance and reported on 01-26-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Center for Genetic Medicine Research, Children's National Medical Center

Dec 01, 2015

- -

Malignant hyperthermia, susceptibility to, 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

May 14, 2024

This missense variant replaces arginine with glutamine at codon 2415 of the RYR1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with congenital myopathy (PMID: 27854218). This variant has been identified in 25/282694 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	.;T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Uncertain	0.52	D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Benign	1.6	L;L
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.2	N;N
REVEL	Uncertain	0.62
Sift	Benign	0.24	T;T
Polyphen		0.99	D;D
Vest4		0.55
MVP		1.0
MPC		0.37
ClinPred		0.24	T
GERP RS		4.0
Varity_R		0.20
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs201584482; hg19: chr19-38990577; COSMIC: COSV62095532;