19-38473699-C-G

Position:

• chr19-38473699-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_000540.3(RYR1):​c.4088C>G​(p.Ala1363Gly) 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 benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000043 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.868

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RYR1. . Gene score misZ 1.918 (greater than the threshold 3.09). Trascript score misZ 3.9788 (greater than threshold 3.09). GenCC has associacion of gene with 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.28162122).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.4088C>G	p.Ala1363Gly	missense_variant	28/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.4088C>G	p.Ala1363Gly	missense_variant	28/106	5	NM_000540.3	ENSP00000352608.2
RYR1	ENST00000355481.8	c.4088C>G	p.Ala1363Gly	missense_variant	28/105	1		ENSP00000347667.3
RYR1	ENST00000599547.6	n.4088C>G		non_coding_transcript_exon_variant	28/80	2		ENSP00000471601.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000439 AC: 6 AN: 136656 Hom.: 0 AF XY: 0.0000677 AC XY: 5 AN XY: 73836

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000414

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000467

Gnomad FIN exome AF: 0.0000714

Gnomad NFE exome AF: 0.0000623

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000431 AC: 6 AN: 1393162 Hom.: 0 Cov.: 33 AF XY: 0.00000583 AC XY: 4 AN XY: 686588

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000402

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000128

Gnomad4 FIN exome AF: 0.0000426

Gnomad4 NFE exome AF: 0.00000186

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

RYR1-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 05, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RYR1 protein function. ClinVar contains an entry for this variant (Variation ID: 496659). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change replaces alanine with glycine at codon 1363 of the RYR1 protein (p.Ala1363Gly). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and glycine. -

Malignant hyperthermia of anesthesia Uncertain:1

Uncertain significance, criteria provided, single submitter

research

CSER _CC_NCGL, University of Washington

Oct 01, 2016

Found in patient having exome sequencing for an unrelated indication. No known history of malignant hyperthermia. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	17
DANN	Benign	0.84
DEOGEN2	Benign	0.34	.;T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.76	T;T
M_CAP	Pathogenic	0.42	D
MetaRNN	Benign	0.28	T;T
MetaSVM	Uncertain	0.043	D
MutationAssessor	Benign	0.0	N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.92	N;N
REVEL	Benign	0.29
Sift	Benign	0.38	T;T
Polyphen		0.90	P;P
Vest4		0.17
MVP		0.91
MPC		0.31
ClinPred		0.062	T
GERP RS		4.0
Varity_R		0.12
gMVP		0.37

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: rs774603798; hg19: chr19-38964339; COSMIC: COSV62092120;