rs118192148

Positions:

• chr19-38584986-G-A
• chr19-38584986-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PS4_Moderate PM2_Supporting PM1 PP3

This summary comes from the ClinGen Evidence Repository: The c.14690G>A variant in RYR1 is a missense variant predicted to cause substitution of glycine by aspartic acid at amino acid 4897. This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.835, which is above the threshold of 0.7, evidence that correlates with impact to RYR1 function (PP3). This variant resides within the pore region (amino acids 4800-4950), of RYR1 that is defined as a mutation hotspot/critical functional domain by the ClinGen Congenital Myopathies VCEP (PM1). This variant has been reported in 2 probands with RYR1-related myopathy (PS4_Moderate; PMIDs: 24561095, 35428369). Additionally, the variant was identified in a third individual with c.9989A>G (p.Asp3330Gly) likely in cis, although variants phasing could not be confirmed at this time (PMID:23919265, SCV000852450.1). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant RYR1-related myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PS4_Moderate, PM1, PM2_Supporting, PP3. (Congenital Myopathies VCEP specifications version 1; 8/7/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA405690291/MONDO:0100150/150

• Frequency: Genomes: not found (cov: 29)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 10.0

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 6 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.14690G>A	p.Gly4897Asp	missense_variant	102/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.14690G>A	p.Gly4897Asp	missense_variant	102/106	5	NM_000540.3	ENSP00000352608	A2

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 29

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

RYR1-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 24, 2017

A different missense substitution at this codon (p.Gly4897Val) has been reported in a family with CCD (PMID: 17226826). However, the clinical significance of this variant is unknown. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This missense change is located in a region of the RYR1 protein where a significant number of previously reported RYR1 missense mutations are found (PMID: 16084090). These observations suggest that a previously unreported missense substitution within this region may affect protein function, but experiments have not been done to test this possibility. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has been reported in several individuals affected with central core disease (CCD) (PMID: 23919265, 24561095). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with aspartic acid at codon 4897 of the RYR1 protein (p.Gly4897Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 17, 2018

- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 26, 2023

The c.14690G>A (p.G4897D) alteration is located in exon 102 (coding exon 102) of the RYR1 gene. This alteration results from a G to A substitution at nucleotide position 14690, causing the glycine (G) at amino acid position 4897 to be replaced by an aspartic acid (D). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). The c.14690G>A alteration has been reported in multiple individuals with clinical features consistent with autosomal dominant RYR1-related myopathy (Gu, 2014; Cotta, 2022; Fusto, 2022, external communication). This amino acid position is highly conserved in available vertebrate species. Based on internal structural analysis, G4897D disrupts the selectivity filter motif which has been shown to be functionally important (Balshaw, 1999; Lefebvre, 2013; Yan, 2015; Wei, 2016; Kushnir, 2020). This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	26
DANN	Benign	0.96
DEOGEN2	Pathogenic	0.96	.;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T;T
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	.;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.8	D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.90
MutPred		0.74		.;Loss of methylation at R4893 (P = 0.058);
MVP		1.0
MPC		1.2
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.92
gMVP		1.0

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: rs118192148; hg19: chr19-39075626;