chr19-38546515-C-T

Variant names:

• chr19-38546515-C-T
• rs794728696
• NM_000540.3:c.12083C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_000540.3(RYR1):​c.12083C>T​(p.Ser4028Leu) variant causes a missense change involving the alteration of a 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 29)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:3
• Conservation: PhyloP100: 7.87

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.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the RYR1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 212 curated pathogenic missense variants (we use a threshold of 10). The gene has 94 curated benign missense variants. Gene score misZ: 1.918 (below the threshold of 3.09). Trascript score misZ: 3.9788 (above the threshold of 3.09). GenCC associations: The gene is linked to 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.842
• PP5: Variant 19-38546515-C-T is Pathogenic according to our data. Variant chr19-38546515-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 201152.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=3, Pathogenic=6}. Variant chr19-38546515-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3	c.12083C>T	p.Ser4028Leu	missense_variant	Exon 88 of 106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.12083C>T	p.Ser4028Leu	missense_variant	Exon 88 of 106	5	NM_000540.3	ENSP00000352608.2

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 29

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:2

Dec 19, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 25, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 04, 2021

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 24, 2019

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Central core myopathy Pathogenic:1 Uncertain:1

Apr 11, 2022

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 20, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed missense variant c.12083C>T (p.Ser4028Leu) in RYR1 gene has been reported previously in heterozygous state in multiple individuals affected with congenital myopathy, with a susceptibility to malignant hyperthermia (Dai et al. 2015; Biancalana et al. 2021). This variant is reported to segregate with the disease in families with dominant disease transmission, and may also occur de novo (Biancalana et al. 2021). Experimental evidence shows that this variant causes channel oxidation and reduces RyR1-calstabin1 binding, and causes leaky channel behavior which is known to cause muscle dysfunction (Kushnir et al. 2020; Yuan et al. 2021). The p.Ser4028Leu variant is absent in gnomAD Exomes database. This variant has been submitted to the ClinVar database as Uncertain Significance / Likely Pathogenic / Pathogenic. Multiple lines of computational evidence (SIFT - damaging; Polyphen - probably damaging; MutationTaster - disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid at this position on RYR1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ser at position 4028 is changed to a Leu changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -

Congenital multicore myopathy with external ophthalmoplegia Pathogenic:1

Jan 11, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RYR1 c.12083C>T (p.Ser4028Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251464 control chromosomes (gnomAD). c.12083C>T has been reported in the literature in multiple individuals affected with Congenital Myopathy and was shown to segregate with the disease in dominant families or to occur de novo in sporadic cases (e.g. Dai_2015, Kushnir_2020, Biancalana_2021, Natera-de Benito_2021). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant increased channel oxidation and reduced RyR1-calstabin1 binding, and was consistent with leaky channel behavior (Kushnir_2020, Yuan_2021). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic and one ClinVar submitter (evaluation after 2014) cites it as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. -

Inborn genetic diseases Pathogenic:1

Nov 03, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.12083C>T (p.S4028L) alteration is located in coding exon 88 of the RYR1 gene. This alteration results from a C to T substitution at nucleotide position 12083, causing the serine (S) at amino acid position 4028 to be replaced by a leucine (L). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been observed in multiple individuals with clinical features of RYR1-related myopathy, including several de novo occurrences (Dai, 2015; Kushnir, 2020; Biancalana, 2021). This amino acid position is highly conserved in available vertebrate species. Experimental evidence derived from studies on muscle biopsies of patients with the variant, demonstrated increased channel oxidation and reduced RyR1-calstabin1 binding, and increased sensitivity to Ca2+-dependent activation consistent with leaky channel behavior (Kushnir, 2020; Yuan, 2021). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

RYR1-related disorder Pathogenic:1

May 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 4028 of the RYR1 protein (p.Ser4028Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant congenital myopathy (PMID: 25987458, 27447704; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 201152). 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 with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Malignant hyperthermia, susceptibility to, 1 Pathogenic:1

Feb 10, 2021

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Centronuclear myopathy Pathogenic:1

Mar 01, 2024

Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.88	.;D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Uncertain	2.8	.;M
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.0	D;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0010	D;D
Polyphen		0.98	D;D
Vest4		0.86
MutPred		0.55		.;Loss of catalytic residue at S4028 (P = 0.2582);
MVP		0.96
MPC		0.51
ClinPred		0.99	D
GERP RS		3.8
Varity_R		0.64
gMVP		0.94

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: rs794728696; hg19: chr19-39037155; COSMIC: COSV62093000;