19-38565290-G-C

Position:

• chr19-38565290-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.12956G>C​(p.Arg4319Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R4319Q) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.802

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.12956G>C	p.Arg4319Pro	missense_variant	91/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.12956G>C	p.Arg4319Pro	missense_variant	91/106	5	NM_000540.3	ENSP00000352608.2
RYR1	ENST00000355481.8	c.12941G>C	p.Arg4314Pro	missense_variant	90/105	1		ENSP00000347667.3
RYR1	ENST00000689936.1	c.1346G>C	p.Arg449Pro	missense_variant	8/22			ENSP00000508999.2
RYR1	ENST00000688602.1	n.1364G>C		non_coding_transcript_exon_variant	9/23			ENSP00000510767.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Nov 27, 2020

This sequence change replaces arginine with proline at codon 4319 of the RYR1 protein (p.Arg4319Pro). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and proline. 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. 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. This variant has not been reported in the literature in individuals with RYR1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	20
DANN	Benign	0.88
DEOGEN2	Uncertain	0.64	.;D
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.73	T;T
M_CAP	Pathogenic	0.99	D
MetaRNN	Uncertain	0.47	T;T
MetaSVM	Uncertain	0.45	D
MutationAssessor	Benign	1.4	.;L
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.9	N;N
REVEL	Uncertain	0.49
Sift	Benign	0.049	D;T
Polyphen		0.89	P;P
Vest4		0.33
MutPred		0.34		.;Loss of helix (P = 0.0017);
MVP		0.99
MPC		0.83
ClinPred		0.59	D
GERP RS		2.7
Varity_R		0.64
gMVP		0.70

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-39055930;