rs112772310

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PP2PP3_Strong

The NM_000540.3(RYR1):c.8638G>A(p.Glu2880Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:1U:3O:1

Conservation

PhyloP100: 9.86

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PP2

Missense variant where missense usually causes diseases, RYR1

PP3

MetaRNN computational evidence supports a deleterious effect, 0.975

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3 linkuse as main transcript	c.8638G>A	p.Glu2880Lys	missense_variant	56/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8 linkuse as main transcript	c.8638G>A	p.Glu2880Lys	missense_variant	56/106	5	NM_000540.3	A2	P21817-1
RYR1	ENST00000355481.8 linkuse as main transcript	c.8638G>A	p.Glu2880Lys	missense_variant	56/105	1		P4	P21817-2
RYR1	ENST00000594335.5 linkuse as main transcript	c.2092G>A	p.Glu698Lys	missense_variant, NMD_transcript_variant	17/49	1
RYR1	ENST00000599547.6 linkuse as main transcript	c.8638G>A	p.Glu2880Lys	missense_variant, NMD_transcript_variant	56/80	2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251146

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135770

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461870

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152110

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:3Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Malignant hyperthermia of anesthesia

Pathogenic:1Uncertain:1

Uncertain significance, reviewed by expert panel	curation	ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	Apr 06, 2023	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 glutamic acid with lysine at codon 2880 of the RYR1 protein, p.(Glu2880Lys). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000009, a frequency consistent with pathogenicity for MHS. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, both of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), however, one of these individuals had a second variant of uncertain significance in RYR1 (p.Glu3290Lys) and was not counted toward PS4, PS4_Supporting was implemented (PMID:19191329). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.901) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PP3_Moderate. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 20, 2016	The p.Glu2880Lys variant in RYR1 has been reported in 2 Swiss individuals with malignant hyperthermia, and segregated with disease in 2 affected relatives from 1 family (Levano 2009). It was absent from large population studies. Computational prediction tools and conservation analysis suggest that the p.Glu2880Lys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Glu2880Lys variant is uncertain. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 22, 2024

Variant summary: RYR1 c.8638G>A (p.Glu2880Lys) results in a conservative amino acid change located in the Ryanodine receptor Ryr domain (IPR003032) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251146 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8638G>A has been reported in the literature in individuals affected with Malignant Hyperthermia Susceptibility without strong evidence of causality (Robinson_2006, Levano_2009). These reports do not provide unequivocal conclusions about association of the variant with Malignant Hyperthermia Susceptibility. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 16917943, 19191329). ClinVar contains an entry for this variant (Variation ID: 133232). Based on the evidence outlined above, the variant was classified as uncertain significance. -

RYR1-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 25, 2022

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 2880 of the RYR1 protein (p.Glu2880Lys). This variant is present in population databases (rs112772310, gnomAD 0.0009%). This missense change has been observed in individual(s) with malignant hyperthermia (PMID: 16917943, 19191329). ClinVar contains an entry for this variant (Variation ID: 133232). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RYR1 protein function. 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. -

not provided

Other:1

not provided, no classification provided

literature only

Leiden Muscular Dystrophy (RYR1)

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.31

Cadd

Uncertain

Dann

Uncertain

1.0

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Pathogenic

0.60

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

0.98

MutationAssessor

Uncertain

2.4

M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-3.8

D;D

REVEL

Pathogenic

0.90

Sift

Uncertain

0.0010

D;D

Polyphen

1.0

D;B

Vest4

0.83

MutPred

0.92

Gain of MoRF binding (P = 0.004);Gain of MoRF binding (P = 0.004);

MVP

0.99

MPC

0.34

ClinPred

0.97

GERP RS

3.1

Varity_R

0.86

gMVP

0.92

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over