19-38502584-G-C

Position:

• chr19-38502584-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_000540.3(RYR1):​c.7692G>C​(p.Lys2564Asn) 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 1,460,476 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.322

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.

• 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.7692G>C	p.Lys2564Asn	missense_variant	48/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.7692G>C	p.Lys2564Asn	missense_variant	48/106	5	NM_000540.3	ENSP00000352608	A2
RYR1	ENST00000355481.8	c.7692G>C	p.Lys2564Asn	missense_variant	48/105	1		ENSP00000347667	P4
RYR1	ENST00000594335.5	c.1146G>C	p.Lys382Asn	missense_variant, NMD_transcript_variant	9/49	1		ENSP00000470927
RYR1	ENST00000599547.6	c.7692G>C	p.Lys2564Asn	missense_variant, NMD_transcript_variant	48/80	2		ENSP00000471601

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460476 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 726584

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

RYR1-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 22, 2022

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) performed at Invitae indicates that this missense variant is not expected to disrupt 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. This missense change has been observed in individual(s) with congenital myopathy (PMID: 27066551). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 2564 of the RYR1 protein (p.Lys2564Asn). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 13, 2023

Identified in a patient with congenital myopathy who also harbored a variant in the SPTLC2 gene (Tian et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27066551) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Uncertain	0.065	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	22
DANN	Benign	0.93
DEOGEN2	Uncertain	0.70	.;D
Eigen	Benign	-0.028
Eigen_PC	Benign	-0.031
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Uncertain	0.72	D;D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	0.94	D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.7	D;D
REVEL	Uncertain	0.47
Sift	Benign	0.088	T;T
Polyphen		0.94	P;P
Vest4		0.75
MutPred		0.46		Loss of methylation at K2564 (P = 0.0013);Loss of methylation at K2564 (P = 0.0013);
MVP		0.93
MPC		0.39
ClinPred		0.85	D
GERP RS		2.9
Varity_R		0.38
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs886038341; hg19: chr19-38993224; COSMIC: COSV100614987;