rs118192126

chr19-38519295-A-Gchr19-38519295-A-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 3P and 8B. PM2 PP2 BP6_Very_Strong

The NM_000540.3(RYR1):c.10100A>G(p.Lys3367Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K3367N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Likely benign reviewed by expert panel P:1 B:1 O:1
• Conservation: PhyloP100: 7.51

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 -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, RYR1
• BP6: Variant 19-38519295-A-G is Benign according to our data. Variant chr19-38519295-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 65956.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-38519295-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.10100A>G	p.Lys3367Arg	missense_variant	67/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.10100A>G	p.Lys3367Arg	missense_variant	67/106	5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.10100A>G	p.Lys3367Arg	missense_variant	67/105	1		P4
RYR1	ENST00000594335.5	c.*843A>G		3_prime_UTR_variant, NMD_transcript_variant	27/49	1
RYR1	ENST00000599547.6	c.*859A>G		3_prime_UTR_variant, NMD_transcript_variant	66/80	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1 Benign:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Central core myopathy Pathogenic:1

Pathogenic, no assertion criteria provided

curation

GeneReviews

May 11, 2010

- -

Malignant hyperthermia, susceptibility to, 1 Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen

Apr 20, 2021

This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions. This sequence variant predicts a substitution of lysine with arginine at codon 3367 of the RYR1 protein, p.(Lys3367Arg). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode without an in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (PMID:16732084). Functional studies in HEK293 cells do not show an increased sensitivity to RYR1 agonists, BS3_Supporting (PMID:32535660). A REVEL score of 0.632 supports neither a pathogenic nor a benign status for this variant. Based on using Bayes to combine criteria this variant is assessed as Likely Benign, (PMID: 29300386). Criteria implemented: BS3_Supporting. -

not provided Other:1

not provided, no classification provided

literature only

Leiden Muscular Dystrophy (RYR1)

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
Cadd	Uncertain	24
Dann	Benign	0.82
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.060
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.85	T;T
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.67	D;D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Benign	2.0	M;M
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Uncertain	0.63
Sift	Benign	0.10	T;T
Polyphen		0.041	B;B
Vest4		0.70
MutPred		0.69		Loss of methylation at K3367 (P = 0.0266);Loss of methylation at K3367 (P = 0.0266);
MVP		1.0
MPC		0.26
ClinPred		0.74	D
GERP RS		3.5
Varity_R		0.27
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.30		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs118192126; hg19: chr19-39009935;