rs371498385

chr19-38468973-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1 PP2

The NM_000540.3(RYR1):c.3389G>A(p.Arg1130His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,614,052 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1130C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 8.10

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 Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a domain B30.2/SPRY 2 (size 195) in uniprot entity RYR1_HUMAN there are 22 pathogenic changes around while only 9 benign (71%) in NM_000540.3
• PP2: Missense variant where missense usually causes diseases, RYR1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.3389G>A	p.Arg1130His	missense_variant	26/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.3389G>A	p.Arg1130His	missense_variant	26/106	5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.3389G>A	p.Arg1130His	missense_variant	26/105	1		P4
RYR1	ENST00000599547.6	c.3389G>A	p.Arg1130His	missense_variant, NMD_transcript_variant	26/80	2

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152074 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000557 AC: 14 AN: 251332 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135862

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: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000280 AC: 41 AN: 1461860 Hom.: 0 Cov.: 31 AF XY: 0.0000316 AC XY: 23 AN XY: 727238

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74406

Gnomad4 AFR AF: 0.000120

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: 0.0000441

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000604

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000576 AC: 7

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 05, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 29, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Central core myopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The missense variant c.3389G>A (p.Arg1130His) in RYR1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant has been reported to the ClinVar database as Uncertain Significance. The p.Arg1130His variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.005660% is reported in gnomAD. The amino acid Arg at position 1130 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg1130His in RYR1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance . -

RYR1-Related Disorders Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 01, 2022

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1130 of the RYR1 protein (p.Arg1130His). This variant is present in population databases (rs371498385, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of congenital myopathy (Invitae). 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: 590513). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

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 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.11
Cadd	Pathogenic	28
Dann	Uncertain	1.0
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Uncertain	0.72	D;D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Uncertain	2.8	M;M
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.4	D;D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0090	D;D
Polyphen		1.0	D;D
Vest4		0.61
MVP		0.97
MPC		1.1
ClinPred		0.65	D
GERP RS		4.3
Varity_R		0.72
gMVP		0.73

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: rs371498385; hg19: chr19-38959613; COSMIC: COSV62089483; COSMIC: COSV62089483;