rs794728696

chr19-38546515-C-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). Synonymous variant affecting the same amino acid position (i.e. S4028S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 29)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:2
• 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 where missense usually causes diseases, RYR1
• 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: {Uncertain_significance=2, Pathogenic=4, Likely_pathogenic=2}. Variant chr19-38546515-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.12083C>T	p.Ser4028Leu	missense_variant	88/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.12083C>T	p.Ser4028Leu	missense_variant	88/106	5	NM_000540.3	A2

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 29

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 24, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Oct 04, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 25, 2015	- -

Congenital multicore myopathy with external ophthalmoplegia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jan 11, 2023

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. -

Central core myopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

MGZ Medical Genetics Center

Apr 11, 2022

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 03, 2023

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 01, 2023

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 10, 2021

- -

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
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
MutationTaster	Benign	1.0	D;D;D
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;