rs111888148

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS4_ModeratePM1PP3_Moderate

This summary comes from the ClinGen Evidence Repository: 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 Arginine with Histidine at codon 530 of the RYR1 protein, p.(Arg530His). The maximum allele frequency for this variant among the six major gnomAD populations is AMR: 0.000145, a frequency consistent with pathogenicity for MHS. This variant has been reported in five unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all 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:19191329, PMID:19191333, PMID:30236257, PMID:35718563). A functional study was published for this variant looking at acidification rates in B-lymphocytes, this assay is not considered a standard assay by the ClinGen RYR1 VCEP for MHS (PMID:27646467). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID:21118704). This variant segregates with MHS in 2 individuals (PMID:19191333). A REVEL score >0.85 supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS4_Moderate, PM1, PP3_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CV133101/MONDO:0007783/012

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:21O:1

Conservation

PhyloP100: 8.03

Publications

25 publications found

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 Gene-Disease associations (from GenCC):

malignant hyperthermia, susceptibility to, 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, Ambry Genetics
congenital multicore myopathy with external ophthalmoplegia
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
RYR1-related myopathy
Inheritance: AR, AD Classification: DEFINITIVE Submitted by: ClinGen
central core myopathy
Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
King-Denborough syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
malignant hyperthermia of anesthesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autosomal recessive centronuclear myopathy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
benign Samaritan congenital myopathy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
congenital myopathy with myasthenic-like onset
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
lethal multiple pterygium syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

RYR1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

PM1

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3 link	c.1589G>A	p.Arg530His	missense_variant	Exon 15 of 106	ENST00000359596.8	NP_000531.2	P21817-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8 link	c.1589G>A	p.Arg530His	missense_variant	Exon 15 of 106	5	NM_000540.3	ENSP00000352608.2		P21817-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152082

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000557

AC:

AN:

251494

AF XY:

0.0000368

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000527

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000287

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33480

American (AMR)

AF:

0.000112

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000261

AC:

AN:

1112010

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152082

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41386

American (AMR)

AF:

0.00

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000232

Hom.:

Bravo

AF:

0.0000680

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:21Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:7Other:1

Jul 28, 2023

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 08, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The RYR1 c.1589G>A; p.Arg530His variant (rs111888148) is reported in the literature in multiple individuals and families affected with malignant hyperthermia (Levano 2009, Miller 2018, Mungunsukh 2019, Robinson 2006, Tsutsumi 2021, Zullo 2009). This variant is found in the general population with an overall allele frequency of 0.006% (14/251,494 alleles) in the Genome Aggregation Database. This variant occurs in the functionally important N-terminal domain, and computational analyses predict that this variant is deleterious (REVEL: 0.93). Functional assays indicate lymphoblastoid cell lines exhibit increased acidification in response to 4-chloro-m-cresol compared to cells expressing wildtype RYR1 (Zullo 2009), although this is not considered a standard assay. Based on available information, this variant is considered to be likely pathogenic. References: Levano S et al. Increasing the number of diagnostic mutations in malignant hyperthermia. Hum Mutat. 2009 Apr;30(4):590-8. PMID: 19191329. Miller DM et al. Genetic epidemiology of malignant hyperthermia in the UK. Br J Anaesth. 2018 Oct;121(4):944-952. PMID: 30236257. Mungunsukh O et al. Estimating prevalence of malignant hyperthermia susceptibility through population genomics data. Br J Anaesth. 2019 Sep;123(3):e461-e463. PMID: 31301762. Robinson R et al. Mutations in RYR1 in malignant hyperthermia and central core disease. Hum Mutat. 2006 Oct;27(10):977-89. PMID: 16917943. Tsutsumi YM et al. Malignant hyperthermia in a 16-day-old infant with congenital diaphragmatic hernia: a case report. J Anesth. 2021 Apr;35(2):311-314. PMID: 33625594. Zullo A et al. Functional characterization of ryanodine receptor (RYR1) sequence variants using a metabolic assay in immortalized B-lymphocytes. Hum Mutat. 2009 Apr;30(4):E575-90. PMID: 19191333. -

RYR1 database

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Jan 30, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP3, PM1, PS3_supporting, PS4_moderate -

Dec 13, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in the heterozygous state in association with malignant hyperthermia in published literature (PMID: 27646467, 19191333); Identified in an infant with malignant hyperthermia who harbored a second pathogenic RYR1 variant on the opposite allele (in trans) (PMID: 33625594); Published functional studies demonstrate that this variant results in altered channel function as compared to controls (PMID: 19191333, 32236737); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27147545, 33767344, 16917943, 19191329, 25637381, 30236257, 30155738, 19191333, 32236737, 34426522, 31589614, 31301762, 34849273, 33146414, 30291343, 27646467, 33625594, 26578207, 37787745) -

Dec 21, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 05, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RYR1: PM1, PS4:Moderate, PM5:Supporting, PS3:Supporting -

Malignant hyperthermia, susceptibility to, 1

Pathogenic:7

Aug 30, 2023

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 12, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Criteria applied: PS4,PS3_SUP,PM2_SUP,PP3 -

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

May 20, 2023

ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen

Significance:Likely pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

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 Arginine with Histidine at codon 530 of the RYR1 protein, p.(Arg530His). The maximum allele frequency for this variant among the six major gnomAD populations is AMR: 0.000145, a frequency consistent with pathogenicity for MHS. This variant has been reported in five unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all 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:19191329, PMID:19191333, PMID:30236257, PMID:35718563). A functional study was published for this variant looking at acidification rates in B-lymphocytes, this assay is not considered a standard assay by the ClinGen RYR1 VCEP for MHS (PMID:27646467). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID:21118704). This variant segregates with MHS in 2 individuals (PMID:19191333). A REVEL score >0.85 supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS4_Moderate, PM1, PP3_Moderate. -

Jan 21, 2025

Color Diagnostics, LLC DBA Color Health

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces arginine with histidine at codon 530 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. This variant occurs in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to malignant hyperthermia susceptibility (PMID: 21118704). It has been shown that immortalized B-lymphocytes from individuals carrying this variant undergo higher acidification after treatment with 4-CmC or ryanodine than B-lymphocytes carrying wild-type RYR1 (PMID: 19191333, 27646467). This variant has been reported in seven families/individuals affected with malignant hyperthermia susceptibility (PMID: 19191329, 19191333, 27646467, 30236257, 33625594, 35718563), including four families/individuals with a personal or family history of a malignant hyperthermia event and a positive in vitro contracture test (PMID: 19191329, 30236257, 35718563) and one individual who carried another pathogenic variant in the RYR1 gene (PMID: 33625594). This variant has been observed in three related individuals affected with malignant hyperthermia susceptibility (PMID: 19191333). This variant has been identified in 14/251494 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Sep 25, 2024

All of Us Research Program, National Institutes of Health

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1589G>A (p.Arg530His) variant, located on the exon 15 of the RYR1 gene, replaces arginine with histidine at codon 530. This missense change has been observed in five unrelated individuals with personal or family histories of a malignant hyperthermia reaction, positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) (PMID:19191329, 19191333, 30236257, 35718563). This variant has been reported to segregate with malignant hyperthermia susceptibility (MHS) in two individuals (PMID:19191333). This variant is located in a mutational hot spot that has been reported to contribute to MHS (PMID: 21118704). Although a functional study found that B-lymphocytes expressing RYR1 variant p.Arg530His displayed higher activity compared with controls, accounting for the MH-susceptible phenotype, this assay is not considered a standard assay by the ClinGen RYR1 Variant Curation Expert Panel for MHS (PMID:27646467). Computational prediction (REVEL >0.85) suggests that this variant may have deleterious impact on protein structure and function. This variant has been classified as likely pathogenic/pathogenic by multiple submitters in ClinVar including the expert review panel (ID: 133101). This variant is rare (14/251494 chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Therefore, the c.1589G>A(p.Arg530His) variant in the RYR1 gene is classified as likely pathogenic. -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS4_Moderate+PM1+PP3_Moderate -

RYR1-related disorder

Pathogenic:2

Aug 06, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The RYR1 c.1589G>A variant is predicted to result in the amino acid substitution p.Arg530His. This variant has been reported to be causative for malignant hyperthermia (MH) in two unrelated families, with functional evidence supporting pathogenicity (Zullo et al. 2009. PubMed ID: 19191333; Robinson et al. 2006. PubMed ID: 16917943). At PreventionGenetics we have observed this variant in the compound heterozygous state in two patients with congenital myopathy. This variant is reported in 0.014% of alleles in individuals of Latino descent in gnomAD. We classify this variant as likely pathogenic for both dominant and recessive RYR1-related disorders. -

Nov 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 530 of the RYR1 protein (p.Arg530His). This variant is present in population databases (rs111888148, gnomAD 0.01%). This missense change has been observed in individuals with autosomal dominant malignant hyperthermia susceptibility (PMID: 19191329, 19191333, 30236257). It has also been observed to segregate with disease in related individuals. This variant has been reported in individual(s) with clinical features of autosomal recessive congenital myopathy (PMID: 26578207); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 133101). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt RYR1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects RYR1 function (PMID: 19191333, 27646467). For these reasons, this variant has been classified as Pathogenic. -

Malignant hyperthermia of anesthesia

Pathogenic:2

Mar 28, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Arg530His variant in RYR1 has been reported in 3 individuals with malignant hyperthermia (MH) and segregated with disease in 2 affected members from 1 family (Zullo 2009 PMID: 19191333, Levano 2009 PMID: 19191329, Miller 2018 PMID: 30236257). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 133101) and has been identified in 0.005% (6/113770) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies support an impact on the protein (Zullo 2009 PMID: 19191333, Hoppe 2016 PMID: 27646467), and computational prediction tools and conservation analysis are consistent with pathogenicity. In addition, this variant is located within the intracellular calcium-release channel domain, which is enriched with pathogenic variation and is considered a critical functional domain (Tilgen 2001 PMID: 11741831). Moreover, this variant has been classified as a diagnostic mutation by the European Malignant Hyperthermia Group (EMHG; https://www.emhg.org/diagnostic-mutations). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant MH. ACMG/AMP criteria applied: PP3, PS3_Moderate, PS4_Supporting, PM1. -

Aug 07, 2022

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: RYR1 c.1589G>A (p.Arg530His) results in a non-conservative amino acid change located in the RIH domain (IPR000699) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251494 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in RYR1 causing Malignant Hyperthermia Susceptibility (5.6e-05 vs 8.8e-05), allowing no conclusion about variant significance. c.1589G>A has been reported in the literature as a heterozygous/compound heterozygous genotype in individuals affected with Malignant Hyperthermia Susceptibility or Neuromuscular Disease (example, Levano_2009, Zullo_2009, Todd_2015, Miller_2018, Kushnir_2020, Herman_2021, Tsutsumi_2021). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function reporting increased acidification rate of lymphoblastoid cells and immortalized B-lymphocytes in response to 4-chloro-mcresol (4-CmC) (example, Zullo_2009, Hoppe_2016). Multiple clinical diagnostic laboratories and an expert panel (ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 with a majority consensus as pathogenic/likely pathogenic (n=9) (VUS, n=2 to include the expert panel). Based on the evidence outlined above, the variant was classified as pathogenic. -

Inborn genetic diseases

Pathogenic:1

Apr 30, 2024

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1589G>A (p.R530H) alteration is located in exon 15 (coding exon 15) of the RYR1 gene. This alteration results from a G to A substitution at nucleotide position 1589, causing the arginine (R) at amino acid position 530 to be replaced by a histidine (H). Based on data from gnomAD, the A allele has an overall frequency of 0.006% (14/251494) total alleles studied. The highest observed frequency was 0.016% (1/6140) of Other alleles. This variant was reported in multiple individuals, and was shown to segregate with disease in one family, with a reported malignant hyperthermia (MH) event, a positive IVCT, and/or a family history of MH (Levano, 2009; Zullo, 2009; Miller, 2018). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy

Pathogenic:1

May 21, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

King Denborough syndrome

Pathogenic:1

Jan 29, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

The p.Arg530His variant in RYR1 has been reported in at least 7 individuals, including 1 Turkish and 1 Swiss individual, with King-Denborough syndrome, segregated with disease in 3 affected relatives from 1 family (PMID: 19191329, 30236257, 30155738, 26578207, 19191333, 16917943), and has been identified in 0.01446% (5/34590) of Latino chromosomes, 0.006152% (1/16256) of African chromosomes, and 0.005274% (6/113770) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs111888148). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population and individuals with this disease are clinically indistinguishable from the general population unless given anesthesia (PMID: 9199552). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a dominant frequency for a disease with clinical variability or reduced penetrance. This variant has also been reported in ClinVar as a VUS, pathogenic, and likely pathogenic variant (Variation ID: 133101). In vitro functional studies provide some evidence that the p.Arg530His variant may impact protein function and may be partially rescued by a RYR1 antagonist (PMID: 19191333). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional variant, resulting in a different amino acid change at the same position, p.Arg530Leu, has been reported as a VUS in association with disease in ClinVar (Variation ID: 212096). The p.Arg530His is located in a region of RYR1 that is essential to regulating the sensitivity of a calcium channel, suggesting that this variant is in a functional domain and supports pathogenicity (PMID: 16084090). In summary, this variant meets criteria to be classified as pathogenic for King-Denborough syndrome in an autosomal dominant manner based on in vitro functional studies, population data, and multiple occurrences of affected individuals with this variant reported in the literature. ACMG/AMP Criteria applied: PS3, PM2, PS4_Moderate, PM1, PP3, PP1 (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

.;D

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.97

D;D

M_CAP

Pathogenic

0.73

MetaRNN

Pathogenic

0.89

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.8

M;M

PhyloP100

8.0

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-4.2

D;D

REVEL

Pathogenic

0.93

Sift

Uncertain

0.0010

D;D

Polyphen

1.0

D;D

Vest4

0.68

MVP

1.0

MPC

1.1

ClinPred

0.92

GERP RS

4.0

Varity_R

0.58

gMVP

0.84

Mutation Taster

=12/88

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

Publications

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rs111888148

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

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