19-38458247-G-A

Position:

• chr19-38458247-G-A

Variant summary

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

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 Aspartic acid with Asparagine at codon 708 of the RYR1 protein, p.(Asp708Asn). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0007, a frequency consistent with pathogenicity for MHS. This variant has been reported in individuals with congenital myopathies inherited in an autosomal recessive pattern. 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 of 0.726 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. No criteria were implemented. LINK:https://erepo.genome.network/evrepo/ui/classification/CA024331/MONDO:0007783/012

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00066 (1 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:9 B:8
• Conservation: PhyloP100: 10.0

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 Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.2122G>A	p.Asp708Asn	missense_variant	18/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.2122G>A	p.Asp708Asn	missense_variant	18/106	5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.2122G>A	p.Asp708Asn	missense_variant	18/105	1		P4
RYR1	ENST00000599547.6	c.2122G>A	p.Asp708Asn	missense_variant, NMD_transcript_variant	18/80	2

Frequencies

GnomAD3 genomes AF: 0.000605 AC: 92 AN: 152154 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000985

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000544 AC: 135 AN: 248290 Hom.: 1 AF XY: 0.000527 AC XY: 71 AN XY: 134784

Gnomad AFR exome AF: 0.0000638

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00369

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000279

Gnomad NFE exome AF: 0.000762

Gnomad OTH exome AF: 0.000658

GnomAD4 exome AF: 0.000664 AC: 970 AN: 1461734 Hom.: 1 Cov.: 33 AF XY: 0.000660 AC XY: 480 AN XY: 727180

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00337

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000319

Gnomad4 NFE exome AF: 0.000758

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.000604 AC: 92 AN: 152272 Hom.: 0 Cov.: 31 AF XY: 0.000604 AC XY: 45 AN XY: 74466

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000660

Gnomad4 NFE AF: 0.000985

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000773 Hom.: 0

Bravo AF: 0.000589

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000466 AC: 4

ExAC AF: 0.000585 AC: 71

EpiCase AF: 0.000818

EpiControl AF: 0.000533

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9 Benign:8

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:4 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 17, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 15, 2020	This variant is associated with the following publications: (PMID: 26245150, 29298851, 30155738, 23553787, 25637381, 23919265, 22473935, 21911697, 20080402, 24195946, 20839240, 32236737) -
Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	May 26, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 10, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 06, 2013	- -

Malignant hyperthermia, susceptibility to, 1 Uncertain:3 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 09, 2022	- -
Uncertain significance, 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 708 of the RYR1 protein, p.(Asp708Asn). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0007, a frequency consistent with pathogenicity for MHS. This variant has been reported in individuals with congenital myopathies inherited in an autosomal recessive pattern. 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 of 0.726 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. No criteria were implemented. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 01, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Apr 02, 2020	The RYR1 c.2122G>A variant is classified as VARIANT OF UNCERTAIN SIGNIFICANCE (PM2, PP3, PS4 - supporting) The RYR1 c.2122G>A variant is a single nucleotide change from a guanine to an adenine at position 2122 which is predicted to change the amino acid aspartic acid at position 708 in the protein to asparagine. This variant is in exon 18 if 106. The variant has been previously described in patients who also carried the Arg2241* variant (PMID: 20080402; PMID: 23919265; PMID: 21911697) (PS4 – supporting). The variant is in dbSNP (rs138874610) and has been reported in population databases (gnomAD 152/279634, 1 homozygote) (PM2). There are conflicting interpretations of pathogenicity in ClinVar including Benign, Likely Benign and VUS by other diagnostic laboratories (Variation ID 159840). Computational predictions support a deleterious effect on the gene or gene product (PP3). -

not specified Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 17, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 29, 2017	Disclaimer: This variant has not undergone full assessment. The following are pr eliminary notes: This variant has been reported in 6 papers in HGMD (classified as DM), with comments suggesting VUS-likely benign. This variant is classified i n ClinVar with 1 star as VUS by University of Chicago, Emory, and Biesecker lab, and is classified as Likely benign by Prevention genetics and CSER_CC_NCGL. The variant has a Max MAF of 0.10% in ExAC (69 alleles) and 0.4% in gnomAD (40 Ashk enazi alleles). Frequency too high for disease incidence. Variant is not present in emhg.org database. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 07, 2022	Variant summary: RYR1 c.2122G>A (p.Asp708Asn) results in a conservative amino acid change located in the first B30.2/SPRY domain (IPR001870) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00054 in 248290 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 6-fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR1 causing Malignant Hyperthermia Susceptibility (MHS) phenotype (8.8e-05), suggesting that the variant is not causal for this phenotype. The association with recessive myopathies cannot be excluded based on this frequency, although the presence of a homozygous occurrence suggests a benign role for these phenotypes as well. The variant, c.2122G>A, has been reported in the literature in individuals affected with a variety of RYR-related myopathies (e.g. Zhou_2010, Klein_2012, Rokach_2015, Colombo_2015, Carmona_2016, Lopez_2016), however in all of these reports the presence of the variant c.6721C>T (p.Arg2241X) was noted, and multiple reports described these two variants in cis, in combination with another (likely) pathogenic missense variants in trans, which explained the recessive inheritance. A publication also reported the absence of allele specific mRNA expression in a patient derived muscle biopsy sample, likely as a result of nonsense-mediated decay caused by the p.Arg2241X stop mutation, further supporting that both variants originate from the same allele (Zhou_2010). In addition, variant co-occurrence analysis in gnomAD indicates that the c.6721C>T (p.Arg2241X) variant is likely found on the same haplotype as c.2122G>A (p.Asp708Asn) in most individuals. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 classifying as VUS (n=4), likely benign (n=4) and benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Congenital myopathy with fiber type disproportion;C0751951:Central core myopathy;C1840365:King Denborough syndrome;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

Feb 22, 2022

- -

RYR1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 21, 2024

- -

Congenital myopathy Benign:1

Likely benign, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	.;D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Uncertain	0.38	D
MutationAssessor	Pathogenic	3.8	H;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-4.6	D;D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.79
MVP		0.99
MPC		1.0
ClinPred		0.32	T
GERP RS		5.0
Varity_R		0.78
gMVP		0.72

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

Other links and lift over

dbSNP: rs138874610; hg19: chr19-38948887; COSMIC: COSV62089062;