rs193922872

Variant names:

• chr19-38580039-T-A
• rs193922872
• NM_000540.3:c.14422T>A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Strong

The NM_000540.3(RYR1):​c.14422T>A​(p.Phe4808Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F4808L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 7.98

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a transmembrane_region Helical; Name=4 (size 16) in uniprot entity RYR1_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000540.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-38580041-C-A is described in Lovd as [Likely_pathogenic].
• PP2: Missense variant in the RYR1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 212 curated pathogenic missense variants (we use a threshold of 10). The gene has 94 curated benign missense variants. Gene score misZ: 1.918 (below the threshold of 3.09). Trascript score misZ: 3.9788 (above the threshold of 3.09). GenCC associations: The gene is linked to 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3	c.14422T>A	p.Phe4808Ile	missense_variant	Exon 100 of 106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.14422T>A	p.Phe4808Ile	missense_variant	Exon 100 of 106	5	NM_000540.3	ENSP00000352608.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not provided Other:1

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RYR1 database

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	23
DANN	Benign	0.95
DEOGEN2	Pathogenic	0.93	.;D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	.;M
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.2	D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.87
MutPred		0.86		.;Loss of stability (P = 0.0782);
MVP		1.0
MPC		0.92
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.91
gMVP		0.96

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: rs193922872; hg19: chr19-39070679;