rs193922837

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_StrongBP4

The NM_000540.3(RYR1):c.10348-6C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000266 in 1,614,248 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

RYR1
NM_000540.3 splice_region, intron

Scores

Splicing: ADA: 0.0001551

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14U:1O:1

Conservation

PhyloP100: -0.101

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PP5

Variant 19-38523211-C-G is Pathogenic according to our data. Variant chr19-38523211-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 132994.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38523211-C-G is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3 link	c.10348-6C>G		splice_region_variant, intron_variant	Intron 68 of 105	ENST00000359596.8	NP_000531.2	P21817-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8 link	c.10348-6C>G		splice_region_variant, intron_variant	Intron 68 of 105	5	NM_000540.3	ENSP00000352608.2		P21817-1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000313

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251458

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000205

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.000627

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000853

AC:

AN:

152360

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14Uncertain:1Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4Other:1

RYR1 database

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Nov 09, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported previously in multiple unrelated individuals with congenital myopathy who also harbored at least one additional RYR1 variant, although phase is not always known (Monnier et al., 2008; Wilmshurst et al., 2010; Bharucha-Goebel et al., 2013; Maggi et al., 2013; Abath Neto et al., 2017; Klein et al., 2012); Published functional studies are suggestive of aberrant splicing (Monnier et al., 2008); In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 25525159, 30932294, 21062345, 16380615, 18765655, 30611313, 23919265, 16917943, 23553484, 20583297, 22473935, 20839240, 23394784, 18253926, 28818389, Bhanudeep2021[Article], 34440373) -

Jan 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 15, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 15, 2015

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RYR1-related disorder

Pathogenic:3

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant affects the canonical splice acceptor site of intron 68 and is therefore predicted to interfere with splicing and result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a compound heterozygous change in patients with congenital myopathy with cores and centronuclear myopathy (PMID: 18253926, 28818389, 30932294, 31069529, 34440373). This variant, in cis with the c.14524G>A (p.Val4842Met) variant, is part of a known haplotype and has been reported as a compound heterozygous change in individuals with RYR1-related myopathies (PMID: 18253926, 20839240). Functional studies demonstrated that the c.10348-6C>G variant resulted in aberrant splicing that introduces a premature termination codon causing the mRNA to undergo NMD (PMID: 18253926, 25525159). The c.10348-6C>G variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.003% (9/282854) and is absent in the homozygous state, thus is presumed to be rare. Based on the available evidence, the c.10348-6C>G variant is classified as Pathogenic. -

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 68 of the RYR1 gene. It does not directly change the encoded amino acid sequence of the RYR1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs193922837, gnomAD 0.03%). This variant has been observed in individual(s) with congenital myopathy (PMID: 18253926, 20839240, 21062345). 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: 132994). Studies have shown that this variant results in retention of intron 68, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 18253926). For these reasons, this variant has been classified as Pathogenic. -

Jul 01, 2023

Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Central core myopathy

Pathogenic:2

Nov 03, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.10348-6C>G variant in RYR1 has been reported in the compound heterozygous state in at least 11 individuals of African descent in cis with p.Val4842Met (suggesting it is a founder variant in Africans) and 2 Chilean individuals with congenital myopathy, and segregated with disease in 4 affected relatives from 2 families (Bharucha-Goebel 2013 PMID: 23553484, Wilmshurst 2010 PMID: 20839240, Monnier 2008 PMID: 18253926, Bevilacqua 2011 PMID: 21062345). It has been reported in ClinVar (Variation ID 132994) and has also been identified in 13/41476 of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies (using patient tissue) showed that the c.10348-6C>G variant resulted in a loss of splicing of intron 68 and the introduction of a premature stop codon (p.His3449ins33fsX54). Both unspliced and spliced transcripts were present, thus indicating an incomplete penetrance of this intronic variation (Monnier 2008 PMID: 18253926, Bevilacqua 2011 PMID: 1062345). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive congenital myopathy. ACMG/AMP Criteria applied: PM2_Supporting, PS3_Supporting, PM3_Very strong, PP1. -

Oct 13, 2021

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

ACMG codes: PS3; PS4M; PM2; PM3; PP5 -

Inborn genetic diseases

Pathogenic:1

Mar 31, 2016

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Pathogenic:1

May 08, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Centronuclear myopathy

Pathogenic:1

Mar 01, 2024

Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PS3+PP1_Strong+PM2+PM3 -

King Denborough syndrome

Pathogenic:1

Jan 29, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The c.10348-6C>G variant in RYR1 has been reported in at least 16 individuals of African descent in cis with p.Val4842Met (suggesting it is a founder variant in Africans) and 2 Chilean individuals with congenital myopathy, segregated with disease in 4 affected relatives from 2 families (PMID: 23553484, 20839240, 18253926, 21062345), and has been identified in 0.03204% (8/24966) of African chromosomes and 0.002822% (1/35438) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs193922837). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported pathogenic and likely pathogenic in ClinVar (Variation ID: 132994). In vitro functional studies provide some evidence that the c.10348-6C>G variant may slightly impact normal splicing and protein levels (PMID: 18253926, 21062345). However, these types of assays may not accurately represent biological function. Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. The presence of this variant in combination with loss of function variants and in at least 12 individuals with congenital myopathy increases the likelihood that the c.10348-6C>G variant is pathogenic (PMID: 23553484, 20839240, 18253926, 21062345). In summary, this variant meets criteria to be classified as pathogenic for congenital myopathy in an autosomal recessive manner based on multiple occurrences with loss of function variants in affected individuals and low prevalence in the general population. ACMG/AMP Criteria applied: PM3_VeryStrong, PM2, BP4, BP7, PP1, PS3_Supporting (Richards 2015). -

Myopathy, RYR1-associated

Pathogenic:1

May 21, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RYR1 c.10348-6C>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Computational tools predict a significant impact on normal splicing: Two predict the variant weakens a canonical 3' acceptor site. One predicts the variant abolishes this site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Monnier_2008). The variant allele was found at a frequency of 2e-05 in 251458 control chromosomes (gnomAD). c.10348-6C>G has been reported in the literature in individuals affected with Myopathy, RYR1-Associated (e.g. Monnier_2008, Bevilacqua_2011, Abath Neto_2017). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 28818389, 18253926, 21062345). ClinVar contains an entry for this variant (Variation ID: 132994). Based on the evidence outlined above, the variant was classified as pathogenic. -

Malignant hyperthermia, susceptibility to, 1

Uncertain:1

Nov 20, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

This variant causes a C to G nucleotide substitution at the -6 position of intron 68 of the RYR1 gene. 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 been identified in 9/282854 chromosomes in the general population by the Genome Aggregation Database (gnomAD). This variant has not been reported in individuals affected with autosomal dominant malignant hyperthermia in the literature, although it is associated with other phenotype(s) (ClinVar variation ID: 132994). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

7.2

DANN

Benign

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00016

dbscSNV1_RF

Benign

0.13

SpliceAI score (max)

0.47

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.47

Position offset: 6

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over