19-38433863-T-C

Position:

• chr19-38433863-T-C

Variant summary

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

The NM_000540.3(RYR1):​c.34T>C​(p.Phe12Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000066 in 151,618 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 30)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.24

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.34T>C	p.Phe12Leu	missense_variant	1/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.34T>C	p.Phe12Leu	missense_variant	1/106	5	NM_000540.3	ENSP00000352608	A2
RYR1	ENST00000355481.8	c.34T>C	p.Phe12Leu	missense_variant	1/105	1		ENSP00000347667	P4
RYR1	ENST00000599547.6	c.34T>C	p.Phe12Leu	missense_variant, NMD_transcript_variant	1/80	2		ENSP00000471601

Frequencies

GnomAD3 genomes AF: 0.00000660 AC: 1 AN: 151618 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000660 AC: 1 AN: 151618 Hom.: 0 Cov.: 30 AF XY: 0.0000135 AC XY: 1 AN XY: 74024

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

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

Aug 18, 2023

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 affected with RYR1-related conditions. This variant is present in population databases (rs370115856, gnomAD 0.01%). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 12 of the RYR1 protein (p.Phe12Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	.;D
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.74	D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Benign	1.3	L;L
MutationTaster	Benign	0.98	D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.8	D;D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0020	D;D
Polyphen		0.95	P;B
Vest4		0.70
MutPred		0.77		Gain of disorder (P = 0.0593);Gain of disorder (P = 0.0593);
MVP		0.98
MPC		0.45
ClinPred		0.98	D
GERP RS		4.8
Varity_R		0.76
gMVP		0.69

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: rs370115856; hg19: chr19-38924503;