rs118192178

Variant names:

• chr19-38500898-C-A
• NM_000540.3:c.7522C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-38500898-C-A
• chr19-38500898-C-G
• chr19-38500898-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_000540.3(RYR1):​c.7522C>A​(p.Arg2508Ser) variant causes a missense change involving the alteration of a non-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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2508G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.388

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 13 ACMG points.

• PM1: In a mutagenesis_site Increases sensitivity to caffeine and 4-chloro-m-cresol. (size 0) in uniprot entity RYR1_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) 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 chrnull-null-null-null is described in UniProt as null.
• 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, 0.976
• PP5: Variant 19-38500898-C-A is Pathogenic according to our data. Variant chr19-38500898-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3237453.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3	c.7522C>A	p.Arg2508Ser	missense_variant	Exon 47 of 106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.7522C>A	p.Arg2508Ser	missense_variant	Exon 47 of 106	5	NM_000540.3	ENSP00000352608.2
RYR1	ENST00000355481.8	c.7522C>A	p.Arg2508Ser	missense_variant	Exon 47 of 105	1		ENSP00000347667.3
RYR1	ENST00000594335.5	n.973C>A		non_coding_transcript_exon_variant	Exon 8 of 49	1		ENSP00000470927.2
RYR1	ENST00000599547.6	n.7522C>A		non_coding_transcript_exon_variant	Exon 47 of 80	2		ENSP00000471601.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 49

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital multicore myopathy with external ophthalmoplegia Pathogenic:1

Nov 30, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	.;D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Uncertain	2.6	M;M
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.6	D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.83
MutPred		0.86		Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);
MVP		1.0
MPC		0.35
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.87
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: chr19-38991538;