19-38485988-C-T

Variant names:

• chr19-38485988-C-T
• rs367543055
• NM_000540.3:c.5333C>T
• RYR1 p.Ser1778Leu

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

0 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 0 classification points (ACMG Germline Pathogenicity v2019). PM2_SupportingBP4

The NM_000540.3(RYR1):c.5333C>T (p.Ser1778Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000137 (AC=2) in the gnomAD database across 1,461,290 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000252. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.S1778= (synonymous): Likely_benign (ClinVar VariationId 544531, 2 stars); p.S1778= (synonymous): Benign (ClinVar VariationId 93273, 2 stars) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.99
• Publications: 2 publications found

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]

RYR1 Gene-Disease associations (from GenCC):

• malignant hyperthermia, susceptibility to, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• RYR1-related myopathy

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, ClinGen
• congenital multicore myopathy with external ophthalmoplegia

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• central core myopathy

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• King-Denborough syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• malignant hyperthermia of anesthesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive centronuclear myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• benign Samaritan congenital myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital myopathy with myasthenic-like onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• lethal multiple pterygium syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACMG Germline Pathogenicity v2019

Specifications for RYR1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 0 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.0000252 — borderline rare for AD+AR gene (base 0.0001, raised to 0.000212 by highest known P/LP ClinVar AF 0.000212) — PM2 supporting.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Supporting).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000540.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	RYR1 NM_000540.3	MANE Select	c.5333C>T p.Ser1778Leu	missense	Exon 34 of 106	Prot: NP_000531.2 UniProt:
	RYR1 NM_001042723.2		c.5333C>T p.Ser1778Leu	missense	Exon 34 of 105	Prot: NP_001036188.1 UniProt:

RYR1 NM_000540.3

MANE Select

HGVSc / HGVSpc.5333C>Tp.Ser1778Leu

Exon rankExon 34 of 106

missense

Prot: NP_000531.2UniProt: P21817-1

RYR1 NM_001042723.2

HGVSc / HGVSpc.5333C>Tp.Ser1778Leu

Exon rankExon 34 of 105

missense

Prot: NP_001036188.1UniProt: P21817-2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	RYR1 ENST00000359596.8	TSL:5MANE Select	c.5333C>T p.Ser1778Leu	missense	Exon 34 of 106	Prot: ENSP00000352608.2 UniProt:
	RYR1 ENST00000355481.8	TSL:1	c.5333C>T p.Ser1778Leu	missense	Exon 34 of 105	Prot: ENSP00000347667.3 UniProt:
	RYR1 ENST00000594335.6	TSL:1	n.5333C>T	non_coding_transcript_exon	Exon 34 of 103	Prot: ENSP00000470927.2 UniProt:

RYR1 ENST00000359596.8

TSL:5MANE Select

HGVSc / HGVSpc.5333C>Tp.Ser1778Leu

Exon rankExon 34 of 106

missense

Prot: ENSP00000352608.2UniProt: P21817-1

RYR1 ENST00000355481.8

TSL:1

HGVSc / HGVSpc.5333C>Tp.Ser1778Leu

Exon rankExon 34 of 105

missense

Prot: ENSP00000347667.3UniProt: P21817-2

RYR1 ENST00000594335.6

TSL:1

HGVSc / HGVSpn.5333C>T

Exon rankExon 34 of 103

non_coding_transcript_exon

Prot: ENSP00000470927.2UniProt: M0R014

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 4 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD2 exomes	AF: 0.00000408	AC:1	Hom:	AN:244950	Cov:
GnomAD4 exome	AF: 0.00000137	AC:2	Hom:0	AN:1461290	Cov:33
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 4 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.0000198	2	100846	0.00	0	179688

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	RYR1-related disorder (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	17
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.010	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	19
DANN	Benign	0.81
DEOGEN2	Uncertain	0.78	D
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.42
FATHMM_MKL	Uncertain	0.97	D
FuncVEP CTI	Benign	0.021
GPN-Star LLR	N/A	-3.7
GPN-Star score	N/A	3.7
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.092	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.48	T
Mutation Taster	N/A	41/59	disease causing
MutationAssessor	Uncertain	2.4	M
PhyloP100	Uncertain	5.0
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Benign	0.23
Sift	Benign	0.061	T
Varity_R	N/A	0.19
VESM-3B	Benign	-6.1

Showing 26 of 26 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs367543055;

hg19: chr19-38976628;

COSMIC: COSV62104099;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar