rs148041292

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP2PP3_Moderate

The NM_000540.3(RYR1):c.7902C>A(p.Asn2634Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000114 in 1,610,608 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. N2634N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:1

Conservation

PhyloP100: -1.84

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 3 ACMG points.

PP2

Missense variant where missense usually causes diseases, RYR1

PP3

MetaRNN computational evidence supports a deleterious effect, 0.84

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3 linkuse as main transcript	c.7902C>A	p.Asn2634Lys	missense_variant	49/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8 linkuse as main transcript	c.7902C>A	p.Asn2634Lys	missense_variant	49/106	5	NM_000540.3	A2	P21817-1
RYR1	ENST00000355481.8 linkuse as main transcript	c.7902C>A	p.Asn2634Lys	missense_variant	49/105	1		P4	P21817-2
RYR1	ENST00000594335.5 linkuse as main transcript	c.1356C>A	p.Asn452Lys	missense_variant, NMD_transcript_variant	10/49	1
RYR1	ENST00000599547.6 linkuse as main transcript	c.7902C>A	p.Asn2634Lys	missense_variant, NMD_transcript_variant	49/80	2

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000279

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000141

AC:

AN:

248868

Hom.:

AF XY:

0.000156

AC XY:

AN XY:

134778

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000202

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:

0.000238

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000112

AC:

163

AN:

1458490

Hom.:

Cov.:

AF XY:

0.000127

AC XY:

AN XY:

725732

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000157

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:

0.000138

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000138

AC:

AN:

152118

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000279

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000216

Hom.:

Bravo

AF:

0.000234

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000988

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 20, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 04, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The RYR1 p.Asn2634Lys variant was not identified in the Cosmic or MutDB databases. The variant was identified in dbSNP (ID: rs148041292) Clinvitae, LOVD 3.0 and ClinVar (reported as a VUS by the Clinical Molecular Genetics Laboratory at John's Hopkins All Children's Hospital and by the ClinSeq Biesecker Lab at NIH for susceptibility to malignant hyperthermia). The variant was identified in control databases in 38 of 280230 chromosomes at a frequency of 0.000136 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 30 of 129078 chromosomes (freq: 0.000232), Latino in 7 of 35436 chromosomes (freq: 0.000198) and other in 1 of 7206 chromosomes (freq: 0.000139); it was not observed in the African, Ashkenazi Jewish, East Asian, European (Finnish), and South Asian populations. The RYR1 p.Asn2634Lys variant was found in an unaffected individual in a study analyzing 870 control participants for variants in genes related to malignant hyperthermia susceptibility (Gonsalves_2014_PMID: 24195946). The p.Asn2634 residue is not highly conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Malignant hyperthermia, susceptibility to, 1

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 18, 2023	This missense variant replaces asparagine with lysine at codon 2634 of the RYR1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown this variant increases sensitivity to RYR1-agonist 4-CmC when expressed in HEK293T cells compared to cells expressing wild-type RYR1 (PMID: 36208971). This variant has been reported in a family affected with malignant hyperthermia susceptibility (PMID: 36208971). This variant has been identified in 38/280230 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 01, 2013	- -

not specified

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Jun 20, 2017

- -

Congenital myopathy with fiber type disproportion;C0751951:Central core myopathy;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

RYR1-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.13

CADD

Benign

0.75

DANN

Benign

0.91

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.24

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.66

MetaRNN

Pathogenic

0.84

D;D

MetaSVM

Uncertain

0.54

MutationAssessor

Uncertain

2.2

M;M

MutationTaster

Benign

0.63

D;D;D

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-4.2

D;D

REVEL

Uncertain

0.49

Sift

Uncertain

0.0090

D;D

Polyphen

0.97

D;P

Vest4

0.75

MutPred

0.42

Loss of catalytic residue at N2634 (P = 7e-04);Loss of catalytic residue at N2634 (P = 7e-04);

MVP

0.98

MPC

0.38

ClinPred

0.34

GERP RS

-3.1

Varity_R

0.25

gMVP

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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