rs35959206

Positions:

• chr19-38570618-C-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000540.3(RYR1):​c.13671C>G​(p.Ser4557Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0431 in 1,613,262 control chromosomes in the GnomAD database, including 1,816 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.042 (204 hom., cov: 32)
  • Exomes 𝑓: 0.043 (1612 hom.)
• Consequence: RYR1 NM_000540.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14 O:1
• Conservation: PhyloP100: -3.14

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 19-38570618-C-G is Benign according to our data. Variant chr19-38570618-C-G is described in ClinVar as [Benign]. Clinvar id is 93253.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38570618-C-G is described in Lovd as [Benign]. Variant chr19-38570618-C-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-3.14 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.07 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.13671C>G	p.Ser4557Ser	synonymous_variant	94/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.13671C>G	p.Ser4557Ser	synonymous_variant	94/106	5	NM_000540.3	ENSP00000352608.2

Frequencies

GnomAD3 genomes AF: 0.0419 AC: 6369 AN: 152094 Hom.: 204 Cov.: 32

Gnomad AFR AF: 0.0114

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0404

Gnomad ASJ AF: 0.0757

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.0365

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0507

Gnomad OTH AF: 0.0502

GnomAD3 exomes AF: 0.0462 AC: 11620 AN: 251466 Hom.: 375 AF XY: 0.0470 AC XY: 6391 AN XY: 135902

Gnomad AFR exome AF: 0.0108

Gnomad AMR exome AF: 0.0265

Gnomad ASJ exome AF: 0.0712

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.0383

Gnomad FIN exome AF: 0.118

Gnomad NFE exome AF: 0.0504

Gnomad OTH exome AF: 0.0559

GnomAD4 exome AF: 0.0433 AC: 63241 AN: 1461050 Hom.: 1612 Cov.: 30 AF XY: 0.0437 AC XY: 31794 AN XY: 726896

Gnomad4 AFR exome AF: 0.0118

Gnomad4 AMR exome AF: 0.0284

Gnomad4 ASJ exome AF: 0.0740

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.0377

Gnomad4 FIN exome AF: 0.112

Gnomad4 NFE exome AF: 0.0425

Gnomad4 OTH exome AF: 0.0457

GnomAD4 genome AF: 0.0418 AC: 6366 AN: 152212 Hom.: 204 Cov.: 32 AF XY: 0.0453 AC XY: 3369 AN XY: 74412

Gnomad4 AFR AF: 0.0114

Gnomad4 AMR AF: 0.0403

Gnomad4 ASJ AF: 0.0757

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.0367

Gnomad4 FIN AF: 0.117

Gnomad4 NFE AF: 0.0507

Gnomad4 OTH AF: 0.0492

Alfa AF: 0.0487 Hom.: 58

Bravo AF: 0.0353

Asia WGS AF: 0.0200 AC: 69 AN: 3478

EpiCase AF: 0.0551

EpiControl AF: 0.0531

ClinVar

Significance: Benign

Submissions summary: Benign:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 29, 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, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 29, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 12, 2013	- -
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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Ser4557Ser in exon 94 of RYR1: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 4.9% (420/8600) o f European American chromosomes from a broad population by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS; dbSNP rs35959206). -

not provided Benign:2 Other:1

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -

Malignant hyperthermia, susceptibility to, 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	Color Diagnostics, LLC DBA Color Health	Mar 29, 2019	- -

Congenital multicore myopathy with external ophthalmoplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 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

- -

Central core myopathy 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	-0.66
CADD	Benign	1.3
DANN	Benign	0.55

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: rs35959206; hg19: chr19-39061258; COSMIC: COSV62097521;