NM_000540.3:c.12986C>A

Variant names:

• chr19-38565320-C-A
• rs118192129
• NM_000540.3:c.12986C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000540.3(RYR1):​c.12986C>A​(p.Ala4329Asp) 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 Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 1.40
• Publications: 16 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: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, Ambry Genetics
• congenital multicore myopathy with external ophthalmoplegia

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• RYR1-related myopathy

  Inheritance: AR, AD Classification: DEFINITIVE Submitted by: ClinGen
• central core myopathy

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964
• PP5: Variant 19-38565320-C-A is Pathogenic according to our data. Variant chr19-38565320-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 65924.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3	c.12986C>A	p.Ala4329Asp	missense_variant	Exon 91 of 106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.12986C>A	p.Ala4329Asp	missense_variant	Exon 91 of 106	5	NM_000540.3	ENSP00000352608.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1016812 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 478924

African (AFR) AF: 0.00 AC: 0 AN: 20524

American (AMR) AF: 0.00 AC: 0 AN: 6280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11440

East Asian (EAS) AF: 0.00 AC: 0 AN: 20504

South Asian (SAS) AF: 0.00 AC: 0 AN: 19010

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18298

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2592

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 879254

Other (OTH) AF: 0.00 AC: 0 AN: 38910

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Central core myopathy Pathogenic:1

May 11, 2010

GeneReviews

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

- -

not provided Other:1

-

RYR1 database

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Benign	20
DANN	Uncertain	0.97
DEOGEN2	Uncertain	0.64	.;D
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.48	T;T
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Benign	1.1	.;L
PhyloP100		1.4
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-2.3	N;N
REVEL	Uncertain	0.64
Sift	Uncertain	0.0010	D;D
Polyphen		0.30	B;B
Vest4		0.76
MutPred		0.77		.;Loss of methylation at R4326 (P = 0.0446);
MVP		0.91
MPC		0.86
ClinPred		0.60	D
GERP RS		2.7
PromoterAI		-0.035	Neutral
Varity_R		0.64
gMVP		0.76
Mutation Taster		=19/81	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs118192129; hg19: chr19-39055960;