rs193922810

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM5PP2PP3_ModeratePP5_Very_Strong

The NM_000540.3(RYR1):c.7291G>A(p.Asp2431Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,614,000 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 Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D2431V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:6U:1O:1

Conservation

PhyloP100: 9.98

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 Pathogenic. Variant got 15 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000540.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-38499984-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 133195.Status of the report is reviewed_by_expert_panel, 3 stars.

PP2

Missense variant where missense usually causes diseases, RYR1

PP3

MetaRNN computational evidence supports a deleterious effect, 0.916

PP5

Variant 19-38499984-G-A is Pathogenic according to our data. Variant chr19-38499984-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 133194.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-38499984-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3 linkuse as main transcript	c.7291G>A	p.Asp2431Asn	missense_variant	45/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8 linkuse as main transcript	c.7291G>A	p.Asp2431Asn	missense_variant	45/106	5	NM_000540.3	A2	P21817-1
RYR1	ENST00000355481.8 linkuse as main transcript	c.7291G>A	p.Asp2431Asn	missense_variant	45/105	1		P4	P21817-2
RYR1	ENST00000594335.5 linkuse as main transcript	c.745G>A	p.Asp249Asn	missense_variant, NMD_transcript_variant	6/49	1
RYR1	ENST00000599547.6 linkuse as main transcript	c.7291G>A	p.Asp2431Asn	missense_variant, NMD_transcript_variant	45/80	2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.00000796

AC:

AN:

251290

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461834

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.0000483

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:

0.0000264

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6Uncertain:1Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Malignant hyperthermia, susceptibility to, 1

Pathogenic:3Uncertain:1

Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	Apr 07, 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 aspartic acid with asparagine at codon 2431 of the RYR1 protein, p.(Asp2431Asn). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.000062, 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, two 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), PS4_Moderate (PMID:11575529, PMID:30236257). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score >0.85 (0.888) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS4_Moderate, PM1, PP3_Moderate. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 27, 2023	This missense variant replaces aspartic acid with asparagine at codon 2431 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Although functional studies have not been reported for this variant, it occurs in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to malignant hyperthermia susceptibility (PMID: 21118704). This variant has been reported in individuals and families affected with malignant hyperthermia susceptibility (PMID: 11575529, 12411786, 15448513, 30236257). This variant has been identified in 2/251290 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 28, 2023	This missense variant replaces aspartic acid with asparagine at codon 2431 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Although functional studies have not been reported for this variant, it occurs in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to malignant hyperthermia susceptibility (PMID: 21118704). This variant has been reported in individuals and families affected with malignant hyperthermia susceptibility (PMID: 11575529, 12411786, 15448513, 30236257). This variant has been identified in 2/251290 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

not provided

Pathogenic:1Other:1

not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 05, 2022	- -

RYR1-related condition

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 07, 2023

The RYR1 c.7291G>A variant is predicted to result in the amino acid substitution p.Asp2431Asn. This variant has been reported in multiple individuals with malignant hyperthermia (Table 2, Sambuughin et al. 2001. PubMed ID: 11575529; Table S1, Robinson et al. 2006. PubMed ID: 16917943; Table 2, Rubegni et al. 2019. PubMed ID: 31517061). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. This variant has been classified as likely pathogenic by an expert panel in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/133194/). An alternate nucleotide change affecting the same amino acid (p.Asp2431Asn) has been reported in multiple families with RYR1-associated disease (Table 3, Miller et al. 2018. PubMed ID: 30236257). This variant is interpreted as likely pathogenic for autosomal dominant RYR1-related disorders and uncertain for autosomal recessive RYR1-related disorders. -

RYR1-Related Disorders

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 16, 2024

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 2431 of the RYR1 protein (p.Asp2431Asn). This variant is present in population databases (rs193922810, gnomAD 0.007%). This missense change has been observed in individual(s) with autosomal dominant malignant hyperthermia (PMID: 11575529). ClinVar contains an entry for this variant (Variation ID: 133194). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR1 protein function. This variant disrupts the p.Asp2431 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16917943, 19648156, 30236257; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Uncertain

0.090

Cadd

Uncertain

Dann

Uncertain

1.0

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.49

MetaRNN

Pathogenic

0.92

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.3

M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-4.7

D;D

REVEL

Pathogenic

0.89

Sift

Benign

0.043

D;D

Polyphen

1.0

D;D

Vest4

0.80

MVP

1.0

MPC

0.30

ClinPred

0.96

GERP RS

4.0

Varity_R

0.53

gMVP

0.96

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