19-38485666-G-T

Variant names:

• chr19-38485666-G-T
• rs1316064829
• NM_000540.3:c.5011G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000359596.8(RYR1):​c.5011G>T​(p.Ala1671Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,360 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1671T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RYR1 ENST00000359596.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.24
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2524171).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000359596.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	NM_000540.3	MANE Select	c.5011G>T	p.Ala1671Ser	missense	Exon 34 of 106	NP_000531.2
	RYR1	NM_001042723.2		c.5011G>T	p.Ala1671Ser	missense	Exon 34 of 105	NP_001036188.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	ENST00000359596.8	TSL:5 MANE Select	c.5011G>T	p.Ala1671Ser	missense	Exon 34 of 106	ENSP00000352608.2
	RYR1	ENST00000355481.8	TSL:1	c.5011G>T	p.Ala1671Ser	missense	Exon 34 of 105	ENSP00000347667.3
	RYR1	ENST00000594335.6	TSL:1	n.5011G>T		non_coding_transcript_exon	Exon 34 of 103	ENSP00000470927.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458360 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 725754

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50148

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111868

Other (OTH) AF: 0.00 AC: 0 AN: 60362

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Malignant hyperthermia, susceptibility to, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.099
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.25	T
MetaSVM	Uncertain	0.23	D
MutationAssessor	Benign	0.69	N
PhyloP100		3.2
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.33
Sift	Benign	0.27	T
Polyphen		0.65	P
Vest4		0.25
MutPred		0.38		Gain of MoRF binding (P = 0.1136)
MVP		0.97
MPC		0.28
ClinPred		0.96	D
GERP RS		1.8
Varity_R		0.097
gMVP		0.27
Mutation Taster		=86/14	polymorphism

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: rs1316064829; hg19: chr19-38976306; COSMIC: COSV100616636;