rs1236057233

Positions:

• chr19-38565403-C-A
• chr19-38565403-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP2

The NM_000540.3(RYR1):​c.13069C>A​(p.Leu4357Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000176 in 1,303,442 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: 0.000018 (0 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 O:1
• Conservation: PhyloP100: 0.227

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 1 ACMG points.

• 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.13069C>A	p.Leu4357Met	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.13069C>A	p.Leu4357Met	missense_variant	91/106	5	NM_000540.3	ENSP00000352608	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000259 AC: 2 AN: 77144 Hom.: 0 AF XY: 0.0000225 AC XY: 1 AN XY: 44362

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000674

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: 0.0000354

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000176 AC: 23 AN: 1303442 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 8 AN XY: 642748

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000391

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: 0.0000211

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 19, 2024

Variant summary: RYR1 c.13069C>A (p.Leu4357Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.6e-05 in 77144 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.13069C>A in individuals affected with Myopathy, RYR1-Associated and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 544446). Based on the evidence outlined above, the variant was classified as uncertain significance. -

RYR1-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 11, 2022

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. ClinVar contains an entry for this variant (Variation ID: 544446). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 4357 of the RYR1 protein (p.Leu4357Met). -

Multiminicore myopathy;C0546264:Congenital myopathy with fiber type disproportion;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

-

Variant classified as Uncertain significance and reported on 09-09-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.086	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Uncertain	0.42	.;T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.35	T;T
M_CAP	Pathogenic	0.98	D
MetaRNN	Uncertain	0.55	D;D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Benign	1.6	.;L
MutationTaster	Benign	0.94	D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.74	N;N
REVEL	Uncertain	0.42
Sift	Uncertain	0.0050	D;D
Polyphen		0.95	P;P
Vest4		0.41
MutPred		0.46		.;Loss of catalytic residue at L4357 (P = 0.0077);
MVP		0.97
MPC		0.71
ClinPred		0.30	T
GERP RS		2.5
Varity_R		0.11
gMVP		0.25

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: rs1236057233; hg19: chr19-39056043;