rs111436401

chr19-38523116-G-Achr19-38523116-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Moderate PP3_Strong PP5

The NM_000540.3(RYR1):c.10347+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000089 in 1,461,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: RYR1 NM_000540.3 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:1
• Conservation: PhyloP100: 9.92

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 Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.00575511 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.9, offset of -36, new splice context is: atgGTgggc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 19-38523116-G-A is Pathogenic according to our data. Variant chr19-38523116-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 224998.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=7, Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.10347+1G>A		splice_donor_variant		ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.10347+1G>A		splice_donor_variant		5	NM_000540.3	A2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250298 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135446

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

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: 0.00000890 AC: 13 AN: 1461468 Hom.: 0 Cov.: 33 AF XY: 0.00000825 AC XY: 6 AN XY: 726988

Gnomad4 AFR exome AF: 0.00

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: 0.00000899

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000239 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 26, 2022	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Previously reported in trans with another variant in multiple individuals with features of RYR1-related neuromuscular disease in the published literature and at GeneDx (Fattori et al., 2015; Farwell et al., 2015 Zecevic et al., 2020; Alkhunaizi et al.,2019); This variant is associated with the following publications: (PMID: 25356970, 31589614, 30652412, 25957634, 32655342) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 12, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Sep 12, 2019	- -

Malignant hyperthermia, susceptibility to, 1 Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	research	Laan Lab, Human Genetics Research Group, University of Tartu	May 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 04, 2023	This variant causes a G to A nucleotide substitution at the +1 position of intron 68 of the RYR1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. To our knowledge, functional studies have not been reported for this variant. Loss of RYR1 function due to truncation variants is not an established disease mechanism for autosomal dominant malignant hyperthermia, although it is associated with other phenotype(s) (ClinVar variation ID: 224998). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia. -

Congenital multicore myopathy with external ophthalmoplegia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Jun 07, 2019

- -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 13, 2013

- -

RYR1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 06, 2024

This sequence change affects a donor splice site in intron 68 of the RYR1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in RYR1 are known to be pathogenic (PMID: 23919265, 25960145, 28818389, 30611313). This variant is present in population databases (rs111436401, gnomAD 0.003%). Disruption of this splice site has been observed in individual(s) with autosomal recessive centronuclear myopathy (PMID: 25957634). 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: 224998). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Congenital myopathy with fiber type disproportion;C0751951:Central core myopathy;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.26
Cadd	Pathogenic	33
Dann	Uncertain	0.99
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.96	D
MutationTaster	Benign	1.0	D;D;D
GERP RS		2.9

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.97		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs111436401; hg19: chr19-39013756; COSMIC: COSV100615467; COSMIC: COSV100615467;