chr19-38433722-T-C

Variant names:

• chr19-38433722-T-C
• rs4632259
• ENST00000594335.6:n.-108T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BA1 BP4 BP7

This summary comes from the ClinGen Evidence Repository: The NM_000540.3:c.-108T>C variant is located in exon 1 (5’ UTR) of the RYR1 gene. The filtering allele frequency (the lower threshold of the 95% CI of 8126/59394, 618 homozygotes) of the c.-108T>C variant in RYR1 is 0.1297 for African/African American chromosomes by gnomAD v4.1, which is higher than the ClinGen Congenital Myopathies VCEP threshold (≥0.00697) for BA1, and therefore meets this criterion (BA1). This variant is not predicted to impact splicing by SpliceAI. In addition, it occurs at a nucleotide that is poorly conserved as shown by the UCSC Genome Browser (BP4, BP7). In summary, the variant meets the criteria to be classified as benign for RYR1-related myopathy. ACMG/AMP criteria met, as specified by the ClinGen Congenital Myopathies VCEP: BA1, BP4, BP7 (ClinGen Congenital Myopathies VCEP specifications version 1; 8/7/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA023868/MONDO:0100150/179

• Frequency:
  • Genomes: 𝑓 0.042 (431 hom., cov: 31)
  • Exomes 𝑓: 0.0085 (253 hom.)
• Consequence: RYR1 NM_000540.3 5_prime_UTR
• Clinical Significance: Benign reviewed by expert panel B:7 O:1
• Conservation: PhyloP100: -0.450
• Publications: 6 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 -10 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: 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.-108T>C		5_prime_UTR_variant	Exon 1 of 106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.-108T>C		5_prime_UTR_variant	Exon 1 of 106	5	NM_000540.3	ENSP00000352608.2

Frequencies

GnomAD3 genomes AF: 0.0414 AC: 6296 AN: 151926 Hom.: 425 Cov.: 31

Gnomad AFR AF: 0.138

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0174

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00174

Gnomad SAS AF: 0.0224

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00206

Gnomad OTH AF: 0.0369

GnomAD4 exome AF: 0.00855 AC: 5607 AN: 656068 Hom.: 253 Cov.: 8 AF XY: 0.00861 AC XY: 3007 AN XY: 349116

African (AFR) AF: 0.134 AC: 2410 AN: 17958

American (AMR) AF: 0.00997 AC: 354 AN: 35518

Ashkenazi Jewish (ASJ) AF: 0.000195 AC: 4 AN: 20538

East Asian (EAS) AF: 0.00183 AC: 62 AN: 33844

South Asian (SAS) AF: 0.0228 AC: 1487 AN: 65096

European-Finnish (FIN) AF: 0.0000762 AC: 3 AN: 39378

Middle Eastern (MID) AF: 0.00789 AC: 21 AN: 2660

European-Non Finnish (NFE) AF: 0.00206 AC: 841 AN: 407424

Other (OTH) AF: 0.0126 AC: 425 AN: 33652

GnomAD4 genome AF: 0.0416 AC: 6330 AN: 152038 Hom.: 431 Cov.: 31 AF XY: 0.0406 AC XY: 3018 AN XY: 74332

African (AFR) AF: 0.138 AC: 5716 AN: 41436

American (AMR) AF: 0.0174 AC: 265 AN: 15264

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

East Asian (EAS) AF: 0.00175 AC: 9 AN: 5146

South Asian (SAS) AF: 0.0224 AC: 108 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00206 AC: 140 AN: 67984

Other (OTH) AF: 0.0374 AC: 79 AN: 2110

Alfa AF: 0.0179 Hom.: 149

Bravo AF: 0.0464

Asia WGS AF: 0.0350 AC: 121 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:2 Other:1

Jun 28, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

RYR1 database

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Congenital multicore myopathy with external ophthalmoplegia Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Malignant hyperthermia, susceptibility to, 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

RYR1-related myopathy Benign:1

Aug 07, 2024

ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000540.3:c.-108T>C variant is located in exon 1 (5’ UTR) of the RYR1 gene. The filtering allele frequency (the lower threshold of the 95% CI of 8126/59394, 618 homozygotes) of the c.-108T>C variant in RYR1 is 0.1297 for African/African American chromosomes by gnomAD v4.1, which is higher than the ClinGen Congenital Myopathies VCEP threshold (≥0.00697) for BA1, and therefore meets this criterion (BA1). This variant is not predicted to impact splicing by SpliceAI. In addition, it occurs at a nucleotide that is poorly conserved as shown by the UCSC Genome Browser (BP4, BP7). In summary, the variant meets the criteria to be classified as benign for RYR1-related myopathy. ACMG/AMP criteria met, as specified by the ClinGen Congenital Myopathies VCEP: BA1, BP4, BP7 (ClinGen Congenital Myopathies VCEP specifications version 1; 8/7/2024). -

Neuromuscular disease, congenital, with uniform type 1 fiber Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Central core myopathy Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.4
DANN	Benign	0.68
PhyloP100		-0.45
PromoterAI		0.10	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs4632259; hg19: chr19-38924362;