19-38565215-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 1P and 18B. PP2 BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_000540.3(RYR1):c.12881C>T(p.Thr4294Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 993,236 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T4294A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0043 (8 hom., cov: 31)
  • Exomes 𝑓: 0.00046 (0 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Benign reviewed by expert panel U:6 B:6
• Conservation: PhyloP100: 0.974

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 -17 ACMG points.

• PP2: Missense variant where missense usually causes diseases, RYR1
• BP4: Computational evidence support a benign effect (MetaRNN=0.08196983).
• BP6: Variant 19-38565215-C-T is Benign according to our data. Variant chr19-38565215-C-T is described in ClinVar as [Benign]. Clinvar id is 159834.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-38565215-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00434 (635/146294) while in subpopulation AFR AF= 0.0147 (601/40838). AF 95% confidence interval is 0.0137. There are 8 homozygotes in gnomad4. There are 298 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.12881C>T	p.Thr4294Met	missense_variant	91/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.12881C>T	p.Thr4294Met	missense_variant	91/106	5	NM_000540.3	A2

Frequencies

GnomAD3 genomes AF: 0.00433 AC: 633 AN: 146188 Hom.: 8 Cov.: 31

Gnomad AFR AF: 0.0147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000952

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00645

Gnomad NFE AF: 0.000213

Gnomad OTH AF: 0.00199

GnomAD3 exomes AF: 0.00336 AC: 1 AN: 298 Hom.: 0 AF XY: 0.00602 AC XY: 1 AN XY: 166

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00350

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000456 AC: 386 AN: 846942 Hom.: 0 Cov.: 30 AF XY: 0.000440 AC XY: 173 AN XY: 392846

Gnomad4 AFR exome AF: 0.0179

Gnomad4 AMR exome AF: 0.00

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: 0.0000973

Gnomad4 OTH exome AF: 0.000819

GnomAD4 genome AF: 0.00434 AC: 635 AN: 146294 Hom.: 8 Cov.: 31 AF XY: 0.00418 AC XY: 298 AN XY: 71230

Gnomad4 AFR AF: 0.0147

Gnomad4 AMR AF: 0.000950

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000213

Gnomad4 OTH AF: 0.00196

Alfa AF: 0.000716 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Uncertain:6 Benign:6

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:2 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 27, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 22, 2020	This variant is associated with the following publications: (PMID: 19807743, 23476141, 28326467, 27663056) -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 23, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	RYR1: PP3, BS1 -

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

Benign, reviewed by expert panel	curation	ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	Mar 17, 2021	This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions. This sequence variant predicts a substitution of Threonine with Methionine at codon 4294 of the RYR1 protein, p.(Thr4294Met). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.0193, which is considered to be too common for a pathogenic variant causing autosomal dominantly inherited MHS, BA1. This variant has been classified as Benign. Criteria implemented: BA1. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 28, 2019	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

RYR1-related disorder Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 13, 2023	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Congenital multicore myopathy with external ophthalmoplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 28, 2019

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Central core myopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 28, 2019

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 04, 2016

- -

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 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 29, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.070
Cadd	Benign	6.4
Dann	Benign	0.95
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.27	T;T
M_CAP	Pathogenic	0.99	D
MetaRNN	Benign	0.082	T;T
MetaSVM	Uncertain	-0.21	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	0.090	N;N
REVEL	Uncertain	0.53
Sift	Benign	0.23	T;T
Polyphen		0.17	B;B
Vest4		0.15
MutPred		0.78		.;Loss of phosphorylation at T4294 (P = 0.0199);
MVP		0.84
MPC		0.76
ClinPred		0.045	T
GERP RS		-1.4
Varity_R		0.016
gMVP		0.26

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: rs587784372; hg19: chr19-39055855;