rs1049117716

Variant names:

• chr19-38577918-G-C
• rs1049117716
• NM_000540.3:c.14173G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.14173G>C variant in RYR1 is a missense variant predicted to cause substitution of valine by leucine at amino acid 4725. The highest population minor allele frequency in gnomAD v4.1 is 0.00001667 (1/59980 alleles) in the Admixed American population, which is lower than the ClinGen Congenital Myopathies VCEP threshold (absent, 1 allele allowed) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.661, which is neither above nor below the thresholds predicting a damaging or benign impact on RYR1 function. In summary, the variant meets the criteria to be classified as uncertain significance for RYR1-related myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PM2_Supporting (ClinGen Congenital Myopathies VCEP specifications version 2; 08/27/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA308120058/MONDO:0100150/150

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RYR1 NM_000540.3 missense, splice_region
• Scores: Splicing: ADA: 0.9993
• Clinical Significance: Uncertain significance reviewed by expert panel U:6
• Conservation: PhyloP100: 9.38
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: 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	c.14173G>C	p.Val4725Leu	missense_variant, splice_region_variant	Exon 98 of 106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.14173G>C	p.Val4725Leu	missense_variant, splice_region_variant	Exon 98 of 106	5	NM_000540.3	ENSP00000352608.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461840 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727218

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: reviewed by expert panel

Submissions by phenotype

RYR1-related disorder Uncertain:2

Jul 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 4725 of the RYR1 protein (p.Val4725Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of autosomal recessive RYR1-related conditions (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 571399). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Jan 05, 2022

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RYR1 c.14173G>C (p.Val4725Leu) missense variant results in the substitution of valine at amino acid position 4725 with leucine. To our knowledge, this variant has not been reported in the peer-reviewed literature. This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Based on the available evidence, the c.14173G>C (p.Val4725Leu) variant is classified as a variant of uncertain significance for RYR1-related disorders. -

Malignant hyperthermia, susceptibility to, 1 Uncertain:1

May 14, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces valine with leucine at codon 4725 of the RYR1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RYR1-related disorders in the literature. This variant has not been identified 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. -

RYR1-related myopathy Uncertain:1

Aug 27, 2024

ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The c.14173G>C variant in RYR1 is a missense variant predicted to cause substitution of valine by leucine at amino acid 4725. The highest population minor allele frequency in gnomAD v4.1 is 0.00001667 (1/59980 alleles) in the Admixed American population, which is lower than the ClinGen Congenital Myopathies VCEP threshold (absent, 1 allele allowed) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.661, which is neither above nor below the thresholds predicting a damaging or benign impact on RYR1 function. In summary, the variant meets the criteria to be classified as uncertain significance for RYR1-related myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PM2_Supporting (ClinGen Congenital Myopathies VCEP specifications version 2; 08/27/2024). -

not provided Uncertain:1

Oct 05, 2021

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital myopathy with fiber type disproportion;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	26
DANN	Benign	0.93
DEOGEN2	Uncertain	0.70	.;D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	.;M
PhyloP100		9.4
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		0.54
MutPred		0.19		.;Loss of methylation at K4724 (P = 0.035);
MVP		1.0
MPC		0.56
ClinPred		0.97	D
GERP RS		4.9
Varity_R		0.54
gMVP		0.95
Mutation Taster		=8/92	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.080		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: rs1049117716; hg19: chr19-39068558;