rs118192173

chr19-38443612-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM5 PP2 PP3_Strong PP5

The NM_000540.3(RYR1):c.325C>T(p.Arg109Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000477 in 1,614,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R109Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:13 U:1 O:1
• Conservation: PhyloP100: 4.18

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 8 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-38443613-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 634440.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.
• PP2: Missense variant where missense usually causes diseases, RYR1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97
• PP5: Variant 19-38443612-C-T is Pathogenic according to our data. Variant chr19-38443612-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 12988.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=5, Pathogenic=7, not_provided=1, Uncertain_significance=1}. Variant chr19-38443612-C-T is described in Lovd as [Pathogenic]. Variant chr19-38443612-C-T is described in Lovd as [Likely_pathogenic]. Variant chr19-38443612-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.325C>T	p.Arg109Trp	missense_variant	4/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.325C>T	p.Arg109Trp	missense_variant	4/106	5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.325C>T	p.Arg109Trp	missense_variant	4/105	1		P4
RYR1	ENST00000599547.6	c.325C>T	p.Arg109Trp	missense_variant, NMD_transcript_variant	4/80	2

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000796 AC: 20 AN: 251250 Hom.: 0 AF XY: 0.0000736 AC XY: 10 AN XY: 135826

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000465 AC: 68 AN: 1461842 Hom.: 0 Cov.: 33 AF XY: 0.0000371 AC XY: 27 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000540

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74442

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000123 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.000107 AC: 13

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:13 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:6 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jan 03, 2017	- -
not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 27, 2022	Published functional studies demonstrate a damaging effect: R109W expressed in the homozygous state results in complete loss of calcium conductance (Zhou et al., 2006); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29298851, 23553787, 17483490, 17365175, 18171678, 27858727, 28818389, 28357410, 16380615, 30155738, 30611313, 31127727, 33646172, 33646171, 32381029, 17033962, 34463354, 31589614, 32528171, 35361824, 27535533, 23826317, 24195946, 28547000, 22473935, 27855725, 23069638, 16084090, 33333461, 33726816, 16940308) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 15, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 07, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	May 26, 2021	- -

Central core myopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 29, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Apr 08, 2022	- -

RYR1-related disorder Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 31, 2023	The RYR1 c.325C>T variant is predicted to result in the amino acid substitution p.Arg109Trp. This variant has been reported in individuals with autosomal recessive core myopathy (Zhou et al. 2006. PubMed ID: 16940308; Abath Neto et al. 2017. PubMed ID: 28818389; Matthews et al. 2018. PubMed ID: 29298851; Table S1, Natera-de Benito et al. 2020. PubMed ID: 33333461). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant has been classified as pathogenic or likely pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/12988/). This variant is interpreted as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 22, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 109 of the RYR1 protein (p.Arg109Trp). This variant is present in population databases (rs118192173, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal recessive congenital myopathy (PMID: 23826317, 28357410; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12988). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR1 protein function. Experimental studies have shown that this missense change affects RYR1 function (PMID: 18171678). For these reasons, this variant has been classified as Pathogenic. -

Congenital multicore myopathy with external ophthalmoplegia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 27, 2005

- -

Congenital myopathy with fiber type disproportion Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Nov 19, 2019

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3. -

Congenital myopathy with fiber type disproportion;C0751951:Central core myopathy;C1840365:King Denborough syndrome;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

Nov 22, 2021

- -

Malignant hyperthermia, susceptibility to, 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jan 11, 2024

This pathogenicity assessment is for autosomal dominant malignant hyperthermia susceptibility phenotype. This missense variant replaces arginine with tryptophan at codon 109 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with malignant hyperthermia susceptibility. This variant has been reported to segregate with autosomal recessive congenital myopathy in several families and has been reported in multiple unrelated individuals affected with congenital myopathy (PMID: 16940308, 23826317, 28357410, 22473935). This variant has been identified in 22/282604 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.45
Cadd	Pathogenic	28
Dann	Uncertain	1.0
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.1	D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.88
MutPred		0.91		Gain of catalytic residue at L107 (P = 0.0119);Gain of catalytic residue at L107 (P = 0.0119);
MVP		1.0
MPC		1.0
ClinPred		0.83	D
GERP RS		4.1
Varity_R		0.60
gMVP		0.95

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: rs118192173; hg19: chr19-38934252; COSMIC: COSV62102591;