19-38433722-T-C

Position:

• chr19-38433722-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP7 BA1 BP4

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

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 Benign. Variant got -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/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.-108T>C		5_prime_UTR_variant	1/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.-108T>C		5_prime_UTR_variant	1/106	5	NM_000540.3	ENSP00000352608	A2
RYR1	ENST00000355481.8	c.-108T>C		5_prime_UTR_variant	1/105	1		ENSP00000347667	P4

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

Gnomad4 AFR exome AF: 0.134

Gnomad4 AMR exome AF: 0.00997

Gnomad4 ASJ exome AF: 0.000195

Gnomad4 EAS exome AF: 0.00183

Gnomad4 SAS exome AF: 0.0228

Gnomad4 FIN exome AF: 0.0000762

Gnomad4 NFE exome AF: 0.00206

Gnomad4 OTH exome AF: 0.0126

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

Gnomad4 AFR AF: 0.138

Gnomad4 AMR AF: 0.0174

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00175

Gnomad4 SAS AF: 0.0224

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00206

Gnomad4 OTH AF: 0.0374

Alfa AF: 0.0130 Hom.: 84

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 28, 2018	- -
not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Congenital multicore myopathy with external ophthalmoplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

Central core myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Malignant hyperthermia, susceptibility to, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, reviewed by expert panel

curation

ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen

Aug 07, 2024

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.4
DANN	Benign	0.68

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs4632259; hg19: chr19-38924362;