rs780322180

Positions:

• chr19-38459238-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_000540.3(RYR1):​c.2260A>G​(p.Ile754Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.32

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 5 ACMG points.

• PM1: In a domain B30.2/SPRY 1 (size 216) in uniprot entity RYR1_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_000540.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RYR1. . Gene score misZ 1.918 (greater than the threshold 3.09). Trascript score misZ 3.9788 (greater than threshold 3.09). GenCC has associacion of gene with King-Denborough syndrome, congenital multicore myopathy with external ophthalmoplegia, autosomal recessive centronuclear myopathy, RYR1-related myopathy, lethal multiple pterygium syndrome, malignant hyperthermia of anesthesia, benign Samaritan congenital myopathy, malignant hyperthermia, susceptibility to, 1, congenital myopathy with myasthenic-like onset, central core myopathy.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.2260A>G	p.Ile754Val	missense_variant	19/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.2260A>G	p.Ile754Val	missense_variant	19/106	5	NM_000540.3	ENSP00000352608	A2
RYR1	ENST00000355481.8	c.2260A>G	p.Ile754Val	missense_variant	19/105	1		ENSP00000347667	P4
RYR1	ENST00000599547.6	c.2260A>G	p.Ile754Val	missense_variant, NMD_transcript_variant	19/80	2		ENSP00000471601

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251446 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135902

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.000163

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461872 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727236

Gnomad4 AFR exome AF: 0.0000299

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: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

RYR1-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2018

This sequence change replaces isoleucine with valine at codon 754 of the RYR1 protein (p.Ile754Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs780322180, ExAC 0.01%). This variant has not been reported in the literature in individuals with RYR1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.0059	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Uncertain	0.43	.;T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.077	D
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Uncertain	0.084	D
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.89	N;N
REVEL	Uncertain	0.50
Sift	Uncertain	0.012	D;D
Polyphen		0.99	D;P
Vest4		0.44
MutPred		0.60		Gain of methylation at R757 (P = 0.1048);Gain of methylation at R757 (P = 0.1048);
MVP		0.93
MPC		0.80
ClinPred		0.61	D
GERP RS		4.4
Varity_R		0.13
gMVP		0.21

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: rs780322180; hg19: chr19-38949878;