19-38463499-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM5 PP2 PP3_Moderate

The NM_000540.3(RYR1):c.2654G>T(p.Arg885Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,650 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R885H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.34

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 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-38463498-C-T is described in Lovd as [Likely_pathogenic].
• PP2: Missense variant where missense usually causes diseases, RYR1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.938

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.2654G>T	p.Arg885Leu	missense_variant	21/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.2654G>T	p.Arg885Leu	missense_variant	21/106	5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.2654G>T	p.Arg885Leu	missense_variant	21/105	1		P4
RYR1	ENST00000599547.6	c.2654G>T	p.Arg885Leu	missense_variant, NMD_transcript_variant	21/80	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000802 AC: 2 AN: 249460 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135060

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460650 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726692

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Central core myopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 27, 2020

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.19
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Uncertain	0.32
Eigen_PC	Benign	0.17
FATHMM_MKL	Benign	0.55	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Uncertain	2.8	M;M
MutationTaster	Benign	0.87	D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-4.6	D;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.84
MutPred		0.74		Gain of loop (P = 0.024);Gain of loop (P = 0.024);
MVP		0.99
MPC		1.1
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.53
gMVP		0.83

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: rs370634440; hg19: chr19-38954139;