rs193922836

chr19-38523111-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The NM_000540.3(RYR1):c.10343C>T(p.Ser3448Phe) 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S3448S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1 O:1
• Conservation: PhyloP100: 7.84

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, RYR1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.10343C>T	p.Ser3448Phe	missense_variant	68/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.10343C>T	p.Ser3448Phe	missense_variant	68/106	5	NM_000540.3	A2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital multicore myopathy with external ophthalmoplegia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 27, 2005

- -

Malignant hyperthermia, susceptibility to, 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Dec 13, 2023

This missense variant replaces serine with phenylalanine at codon 3448 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.85, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with autosomal dominant malignant hyperthermia in the literature, although it is associated with other phenotype(s) (ClinVar variation ID: 12991). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia. -

not provided Other:1

not provided, no classification provided

literature only

Leiden Muscular Dystrophy (RYR1)

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
Cadd	Uncertain	23
Dann	Benign	0.97
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.7	D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.85
MutPred		0.79		Loss of disorder (P = 0.0352);Loss of disorder (P = 0.0352);
MVP		0.95
MPC		0.41
ClinPred		1.0	D
GERP RS		2.9
Varity_R		0.79
gMVP		0.84

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: rs193922836; hg19: chr19-39013751;