19-38448768-T-C

Position:

• chr19-38448768-T-C

Variant summary

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

This summary comes from the ClinGen Evidence Repository: The variant NM_000540.3:c.1077T>C in RYR1 is a synonymous (silent) variant (p.Ala359=). The filtering allele frequency (the lower threshold of the 95% CI of 19809/19952, 9835 homozygotes) of the c.1077T>C variant in RYR1 is 0.9807 for East Asian 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). The c.1077T>C (p.Ala359=) variant is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by UCSC Genome Browser (BP4, BP7). In summary, the variant meets criteria to be classified as benign. ACMG/AMP criteria met, as specified by the congenital myopathies VCEP: BA1, BP4, BP7 (ClinGen Congenital Myopathies VCEP specifications version 1; 8/7/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA023860/MONDO:0100150/179

• Frequency:
  • Genomes: 𝑓 0.90 (62123 hom., cov: 33)
  • Exomes 𝑓: 0.88 (564635 hom.)
• Consequence: RYR1 NM_000540.3 synonymous
• Clinical Significance: Benign reviewed by expert panel B:20 O:1
• Conservation: PhyloP100: -8.45

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.1077T>C	p.Ala359Ala	synonymous_variant	11/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.1077T>C	p.Ala359Ala	synonymous_variant	11/106	5	NM_000540.3	ENSP00000352608.2
RYR1	ENST00000355481.8	c.1077T>C	p.Ala359Ala	synonymous_variant	11/105	1		ENSP00000347667.3
RYR1	ENST00000599547.6	n.1077T>C		non_coding_transcript_exon_variant	11/80	2		ENSP00000471601.2

Frequencies

GnomAD3 genomes AF: 0.902 AC: 137302 AN: 152164 Hom.: 62084 Cov.: 33

Gnomad AFR AF: 0.933

Gnomad AMI AF: 0.942

Gnomad AMR AF: 0.925

Gnomad ASJ AF: 0.905

Gnomad EAS AF: 0.990

Gnomad SAS AF: 0.764

Gnomad FIN AF: 0.938

Gnomad MID AF: 0.880

Gnomad NFE AF: 0.876

Gnomad OTH AF: 0.899

GnomAD3 exomes AF: 0.887 AC: 222943 AN: 251346 Hom.: 99377 AF XY: 0.879 AC XY: 119448 AN XY: 135876

Gnomad AFR exome AF: 0.930

Gnomad AMR exome AF: 0.916

Gnomad ASJ exome AF: 0.912

Gnomad EAS exome AF: 0.993

Gnomad SAS exome AF: 0.755

Gnomad FIN exome AF: 0.933

Gnomad NFE exome AF: 0.879

Gnomad OTH exome AF: 0.899

GnomAD4 exome AF: 0.878 AC: 1283273 AN: 1461822 Hom.: 564635 Cov.: 66 AF XY: 0.874 AC XY: 635388 AN XY: 727210

Gnomad4 AFR exome AF: 0.931

Gnomad4 AMR exome AF: 0.918

Gnomad4 ASJ exome AF: 0.907

Gnomad4 EAS exome AF: 0.991

Gnomad4 SAS exome AF: 0.757

Gnomad4 FIN exome AF: 0.930

Gnomad4 NFE exome AF: 0.876

Gnomad4 OTH exome AF: 0.888

GnomAD4 genome AF: 0.902 AC: 137400 AN: 152282 Hom.: 62123 Cov.: 33 AF XY: 0.903 AC XY: 67243 AN XY: 74462

Gnomad4 AFR AF: 0.933

Gnomad4 AMR AF: 0.925

Gnomad4 ASJ AF: 0.905

Gnomad4 EAS AF: 0.990

Gnomad4 SAS AF: 0.764

Gnomad4 FIN AF: 0.938

Gnomad4 NFE AF: 0.876

Gnomad4 OTH AF: 0.898

Alfa AF: 0.884 Hom.: 21474

Bravo AF: 0.906

Asia WGS AF: 0.874 AC: 3042 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:20 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:8

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 03, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Ala359Ala in exon 11 of RYR1: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 12.4% (1063/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs10406027). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 22, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 04, 2016	- -

Congenital multicore myopathy with external ophthalmoplegia Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

Malignant hyperthermia, susceptibility to, 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 29, 2019	- -
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:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not provided Benign:1 Other:1

not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

RYR1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

RYR1-related myopathy Benign:1

Benign, reviewed by expert panel

curation

ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen

Aug 07, 2024

The variant NM_000540.3:c.1077T>C in RYR1 is a synonymous (silent) variant (p.Ala359=). The filtering allele frequency (the lower threshold of the 95% CI of 19809/19952, 9835 homozygotes) of the c.1077T>C variant in RYR1 is 0.9807 for East Asian 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). The c.1077T>C (p.Ala359=) variant is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by UCSC Genome Browser (BP4, BP7). In summary, the variant meets criteria to be classified as benign. ACMG/AMP criteria met, as specified by the 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

- -

King Denborough syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

Congenital myopathy with fiber type disproportion;C1840365:King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 11, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.024
DANN	Benign	0.49

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

Publications

LitVar

Other links and lift over

dbSNP: rs10406027; hg19: chr19-38939408; COSMIC: COSV62105060;