chr19-38463448-G-A

Variant names:

• chr19-38463448-G-A
• rs750938678
• NM_000540.3:c.2603G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_000540.3(RYR1):​c.2603G>A​(p.Arg868His) variant causes a missense change. The variant allele was found at a frequency of 0.000258 in 1,613,936 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R868C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00027 (1 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:5
• Conservation: PhyloP100: 4.96
• Publications: 3 publications found

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

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.057513326).
• BP6: Variant 19-38463448-G-A is Benign according to our data. Variant chr19-38463448-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 419631.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000171 (26/152282) while in subpopulation SAS AF = 0.00269 (13/4826). AF 95% confidence interval is 0.00159. There are 0 homozygotes in GnomAd4. There are 18 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000540.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	NM_000540.3	MANE Select	c.2603G>A	p.Arg868His	missense	Exon 21 of 106	NP_000531.2
	RYR1	NM_001042723.2		c.2603G>A	p.Arg868His	missense	Exon 21 of 105	NP_001036188.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	ENST00000359596.8	TSL:5 MANE Select	c.2603G>A	p.Arg868His	missense	Exon 21 of 106	ENSP00000352608.2
	RYR1	ENST00000355481.8	TSL:1	c.2603G>A	p.Arg868His	missense	Exon 21 of 105	ENSP00000347667.3
	RYR1	ENST00000594335.6	TSL:1	n.2603G>A		non_coding_transcript_exon	Exon 21 of 103	ENSP00000470927.2

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152164 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000662 AC: 166 AN: 250922 AF XY: 0.000553

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00226

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.000268 AC: 391 AN: 1461654 Hom.: 1 Cov.: 33 AF XY: 0.000305 AC XY: 222 AN XY: 727146

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.00195 AC: 87 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00289 AC: 249 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53232

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000351 AC: 39 AN: 1111978

Other (OTH) AF: 0.000199 AC: 12 AN: 60388

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152282 Hom.: 0 Cov.: 31 AF XY: 0.000242 AC XY: 18 AN XY: 74464

African (AFR) AF: 0.0000241 AC: 1 AN: 41562

American (AMR) AF: 0.000523 AC: 8 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68020

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000153 Hom.: 0

Bravo AF: 0.000162

ExAC AF: 0.000610 AC: 74

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2 Benign:1

Sep 12, 2024

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RYR1 c.2603G>A (p.Arg868His) results in a non-conservative amino acid change located in the Ryanodine receptor Ryr domain (IPR003032) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00066 in 250922 control chromosomes, predominantly at a frequency of 0.0026 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in RYR1 causing Myopathy, RYR1-Associated phenotype. c.2603G>A has been reported in the literature in one individual affected with Myopathy, RYR1-Associated (Snoeck_2015). These report does not provide unequivocal conclusions about association of the variant with Myopathy, RYR1-Associated. 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: 36983702, 25960145). ClinVar contains an entry for this variant (Variation ID: 419631). Based on the evidence outlined above, the variant was classified as likely benign.

Mar 27, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The R868H variant has been previously reported in an individual with central core disease, however, this variant was noted to be inherited from an asymptomatic parent (Snoeck et al., 2015). The R868H variant is observed in 43/16330 (0.26%) alleles from individuals of South Asian background in large population cohorts, and 1 homozygous individual undergoing testing at GeneDx (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved in mammals, and in silico analysis predicts this variant is probably damaging to the protein structure/function.

Jan 22, 2020

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Arg868His variant in RYR1 has been reported in one individual with Central Core Disease, the individual's asymptomatic parent, and 1 homozygous individual undergoing genetic testing through GeneDx (PMID: 25960145; Variation ID: 419631), and has been identified in 0.2614% (80/30610) of South Asian chromosomes, 0.2258% (80/35428) of Latino chromosomes, and 0.002327% (3/128944) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs750938678). This variant has also been reported as a VUS and likely benign variant in ClinVar (Variation ID: 419631). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. One additional variant, resulting in a different amino acid change at the same position, p.Arg868Cys, has been reported as a VUS in association with disease in ClinVar (Variation ID: 590504). In summary, while the clinical significance of the p.Arg868His variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BS1 (Richards 2015).

RYR1-related disorder Uncertain:1 Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 05, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The RYR1 c.2603G>A variant is predicted to result in the amino acid substitution p.Arg868His. This variant has been previously reported as a variant of uncertain significance in single patient with central core disease, but the variant was also found heterozygous in the asymptomatic parent (Snoeck et al. 2015. PubMed ID: 25960145). The c.2603G>A variant has an allele frequency of 0.26% in individuals of South Asian descent in gnomAD and has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/419631/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

not provided Uncertain:1 Benign:1

May 24, 2023

Revvity Omics, Revvity

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 11, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Congenital multicore myopathy with external ophthalmoplegia Uncertain:1

Aug 02, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Inborn genetic diseases Benign:1

Feb 11, 2025

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Malignant hyperthermia, susceptibility to, 1 Benign:1

Aug 02, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.058	T
MetaSVM	Uncertain	0.54	D
MutationAssessor	Benign	0.81	L
PhyloP100		5.0
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.43
Sift	Benign	0.038	D
Polyphen		1.0	D
Vest4		0.50
MutPred		0.59		Loss of helix (P = 0.0093)
MVP		1.0
MPC		1.1
ClinPred		0.099	T
GERP RS		3.9
Varity_R		0.48
gMVP		0.58
Mutation Taster		=10/90	disease causing

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

Other links and lift over

dbSNP: rs750938678; hg19: chr19-38954088; COSMIC: COSV62092076; COSMIC: COSV62092076;