19-38566975-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000540.3(RYR1):c.13502C>T(p.Pro4501Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00169 in 1,596,762 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts 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. P4501T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0057 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0013 (12 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Benign reviewed by expert panel B:14
• Conservation: PhyloP100: 1.42

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, RYR1
• BP4: Computational evidence support a benign effect (MetaRNN=0.008817822).
• BP6: Variant 19-38566975-C-T is Benign according to our data. Variant chr19-38566975-C-T is described in ClinVar as [Benign]. Clinvar id is 224403.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-38566975-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00565 (860/152206) while in subpopulation AFR AF= 0.0181 (751/41532). AF 95% confidence interval is 0.017. There are 2 homozygotes in gnomad4. There are 414 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.13502C>T	p.Pro4501Leu	missense_variant	92/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.13502C>T	p.Pro4501Leu	missense_variant	92/106	5	NM_000540.3	A2

Frequencies

GnomAD3 genomes AF: 0.00561 AC: 853 AN: 152088 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.0180

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000735

Gnomad OTH AF: 0.00288

GnomAD3 exomes AF: 0.00213 AC: 461 AN: 216354 Hom.: 6 AF XY: 0.00186 AC XY: 217 AN XY: 116524

Gnomad AFR exome AF: 0.0183

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.000852

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00281

Gnomad FIN exome AF: 0.0000551

Gnomad NFE exome AF: 0.000694

Gnomad OTH exome AF: 0.00165

GnomAD4 exome AF: 0.00128 AC: 1845 AN: 1444556 Hom.: 12 Cov.: 32 AF XY: 0.00126 AC XY: 900 AN XY: 716860

Gnomad4 AFR exome AF: 0.0193

Gnomad4 AMR exome AF: 0.00183

Gnomad4 ASJ exome AF: 0.000543

Gnomad4 EAS exome AF: 0.0000256

Gnomad4 SAS exome AF: 0.00271

Gnomad4 FIN exome AF: 0.0000768

Gnomad4 NFE exome AF: 0.000689

Gnomad4 OTH exome AF: 0.00169

GnomAD4 genome AF: 0.00565 AC: 860 AN: 152206 Hom.: 2 Cov.: 31 AF XY: 0.00556 AC XY: 414 AN XY: 74410

Gnomad4 AFR AF: 0.0181

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000735

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.00285 Hom.: 0

Bravo AF: 0.00626

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.0157 AC: 69

ESP6500EA AF: 0.000931 AC: 8

ExAC AF: 0.00245 AC: 296

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: reviewed by expert panel

Submissions by phenotype

Malignant hyperthermia, susceptibility to, 1 Benign:4

Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 01, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 15, 2018	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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, reviewed by expert panel	curation	ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	Mar 16, 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 Proline with Leucine at codon 4501 of the RYR1 protein, p.(Pro4501Leu). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.0181, 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. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 03, 2022	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 13, 2016	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	RYR1: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 27, 2018	This variant is associated with the following publications: (PMID: 24195946, 28326467, 22995991, 21795085, 20981092, 19191329, 27884173, 28750945, 30611313) -

RYR1-related disorder Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jun 19, 2019	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 08, 2016

- -

Congenital multicore myopathy with external ophthalmoplegia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 15, 2018

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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Central core myopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Neuromuscular disease, congenital, with uniform type 1 fiber Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 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

Jul 29, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	19
Dann	Benign	0.80
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.86	D;D
MetaRNN	Benign	0.0088	T;T
MetaSVM	Uncertain	-0.069	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.6	D;D
REVEL	Uncertain	0.42
Sift	Benign	0.059	T;T
Polyphen		0.94	P;P
Vest4		0.36
MVP		0.84
MPC		0.58
ClinPred		0.033	T
GERP RS		3.6
Varity_R		0.15
gMVP		0.56

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: rs73933023; hg19: chr19-39057615;