VCV000328993.14 - ClinVar

NM_000540.3(RYR1):c.577T>A (p.Ser193Thr)

Germline

Reviewed by expert panel

Reviewed by expert panel. Learn more about how ClinVar calculates review status.

Uncertain Significance

for RYR1-related myopathy

Classification is based on the expert panel submission

Aug 2024 by ClinGen Congenital Myopathies Variant Curation Expert Panel…

The classification is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

FDA Recognized Database

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000540.3(RYR1):c.577T>A (p.Ser193Thr)

Variation ID: 328993 Accession: VCV000328993.14

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19q13.2 19: 38444623 (GRCh38) [ NCBI UCSC ] 19: 38935263 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Dec 6, 2016	Jan 13, 2025	Aug 27, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000540.3:c.577T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000531.2:p.Ser193Thr	missense
NM_001042723.2:c.577T>A	NP_001036188.1:p.Ser193Thr	missense
NC_000019.10:g.38444623T>A
NC_000019.9:g.38935263T>A
NG_008866.1:g.15924T>A
LRG_766:g.15924T>A
LRG_766t1:c.577T>A	LRG_766p1:p.Ser193Thr

... more HGVS ... less HGVS

Protein change

S193T

Other names

NM_000540.3(RYR1):c.577T>A
p.Ser193Thr

Canonical SPDI

NC_000019.10:38444622:T:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Links

ClinGen: CA10642702 dbSNP: rs886054379 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
RYR1		No evidence available	No evidence available	GRCh38 GRCh37	9739	10083

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Central core myopathy	Uncertain significance (1)	criteria provided, single submitter	Jun 14, 2016	RCV000312732.5
Neuromuscular disease, congenital, with uniform type 1 fiber	Uncertain significance (1)	criteria provided, single submitter	Jun 14, 2016	RCV000347556.5
Malignant hyperthermia of anesthesia	Uncertain significance (1)	criteria provided, single submitter	Jun 14, 2016	RCV000367447.5
Multiminicore myopathy	Uncertain significance (1)	criteria provided, single submitter	Jun 14, 2016	RCV000391552.5
RYR1-related disorder	Uncertain significance (1)	criteria provided, single submitter	Aug 28, 2021	RCV001216385.7
Central core myopathy Congenital multicore myopathy with external ophthalmoplegia Congenital myopathy with fiber type disproportion King Denborough syndrome Malignant hyperthermia, susceptibility to, 1	Uncertain significance (1)	criteria provided, single submitter	Aug 19, 2021	RCV002495038.1
Malignant hyperthermia, susceptibility to, 1	Uncertain significance (1)	criteria provided, single submitter	Jul 10, 2023	RCV003995863.2
RYR1-related myopathy	Uncertain significance (1)	reviewed by expert panel	Aug 27, 2024	RCV004992176.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain Significance (Aug 27, 2024) C Contributing to aggregate classification	reviewed by expert panel (ClinGen CongenMyopathy ACMG Specifications RYR1 AD V2.0.0) Method: curation	RYR1-related myopathy (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen FDA Recognized Database Accession: SCV005619839.1 First in ClinVar: Jan 13, 2025 Last updated: Jan 13, 2025	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/72d5c8c2-18b7-479a-b37a-6925d3c3c152 Comment: The c.577T>A variant in RYR1 is a missense variant predicted to cause substitution of serine by threonine at amino acid 193 (p.Ser193Thr). The highest population … (more) The c.577T>A variant in RYR1 is a missense variant predicted to cause substitution of serine by threonine at amino acid 193 (p.Ser193Thr). The highest population minor allele frequency in gnomAD v4.1 is 0.00002712 (32/1179992) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). The REVEL score is 0.78, which is greater than the threshold of ≥ 0.7 set by the CM VCEP (PP3). In summary, this variant meets the criteria to be classified as uncertain significance for AD/AR RYR1-related myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PP3. (ClinGen Congenital Myopathies VCEP specifications version 2; 08/27/2024) (less)
Uncertain significance (Jun 14, 2016) N Not contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Malignant Hyperthermia Susceptibility Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000411841.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Uncertain significance (Jun 14, 2016) N Not contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Multiminicore Disease Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000411839.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Uncertain significance (Jun 14, 2016) N Not contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Congenital Neuromuscular Disease with Uniform Type 1 Fiber Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000411838.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Uncertain significance (Jun 14, 2016) N Not contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Central Core Disease Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000411840.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Uncertain significance (Aug 19, 2021) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Central core myopathy Malignant hyperthermia, susceptibility to, 1 Congenital myopathy 4A, autosomal dominant Congenital multicore myopathy with external ophthalmoplegia King Denborough syndrome Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002782495.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain significance (Aug 28, 2021) N Not contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	RYR1-related disorder Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001388181.4 First in ClinVar: Jul 16, 2020 Last updated: Feb 07, 2023	Comment: This sequence change replaces serine with threonine at codon 193 of the RYR1 protein (p.Ser193Thr). The serine residue is highly conserved and there is a … (more) This sequence change replaces serine with threonine at codon 193 of the RYR1 protein (p.Ser193Thr). The serine residue is highly conserved and there is a small physicochemical difference between serine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 328993). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. (less)
Uncertain Significance (Jul 10, 2023) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Malignant hyperthermia, susceptibility to, 1 (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004817860.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Comment: This missense variant replaces serine with threonine at codon 193 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on … (more) This missense variant replaces serine with threonine at codon 193 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RYR1-related disorders in the literature. This variant has been identified in 3/282310 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less) Number of individuals with the variant: 4 Zygosity: Single Heterozygote

Comment:

The c.577T>A variant in RYR1 is a missense variant predicted to cause substitution of serine by threonine at amino acid 193 (p.Ser193Thr). The highest population minor allele frequency in gnomAD v4.1 is 0.00002712 (32/1179992) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). The REVEL score is 0.78, which is greater than the threshold of ≥ 0.7 set by the CM VCEP (PP3). In summary, this variant meets the criteria to be classified as uncertain significance for AD/AR RYR1-related myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PP3. (ClinGen Congenital Myopathies VCEP specifications version 2; 08/27/2024)

Comment:

This sequence change replaces serine with threonine at codon 193 of the RYR1 protein (p.Ser193Thr). The serine residue is highly conserved and there is a small physicochemical difference between serine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 328993). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

Comment:

This missense variant replaces serine with threonine at codon 193 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RYR1-related disorders in the literature. This variant has been identified in 3/282310 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/72d5c8c2-18b7-479a-b37a-6925d3c3c152	-	-	-	-

Text-mined citations for rs886054379 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Mar 16, 2025

ClinVar Genomic variation as it relates to human health

NM_000540.3(RYR1):c.577T>A (p.Ser193Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs886054379 ...