This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
ClinVar Genomic variation as it relates to human health
NM_000540.3(RYR1):c.7880T>G (p.Val2627Gly)
Germline
Classification
Help
criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.
Uncertain significance
11 out of 11 submissions contributed to this classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
11
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000540.3(RYR1):c.7880T>G (p.Val2627Gly)
Variation ID: 590599 Accession: VCV000590599.19
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 19q13.2 19: 38502924 (GRCh38) [ NCBI UCSC ] 19: 38993564 (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 Nov 20, 2018 Sep 6, 2025 Nov 19, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000540.3:c.7880T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000531.2:p.Val2627Gly missense NM_001042723.2:c.7880T>G NP_001036188.1:p.Val2627Gly missense NC_000019.10:g.38502924T>G NC_000019.9:g.38993564T>G NG_008866.1:g.74225T>G LRG_766:g.74225T>G LRG_766t1:c.7880T>G LRG_766p1:p.Val2627Gly - Protein change
- V2627G
- Other names
- -
- Canonical SPDI
- NC_000019.10:38502923:T:G
-
Global minor allele
frequency (GMAF) HelpThe 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.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00002
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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 |
9971 | 10326 | |
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. |
|---|---|---|---|---|
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
May 23, 2023 | RCV000721681.8 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Jan 12, 2018 | RCV001127919.4 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Aug 6, 2024 | RCV001127918.7 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Nov 20, 2023 | RCV001127920.6 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Nov 1, 2021 | RCV001243513.4 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Oct 8, 2021 | RCV002485828.1 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Jan 8, 2024 | RCV003318384.3 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Nov 19, 2024 | RCV005056478.1 |
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. |
Expand all rows
Collapse all rows
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
(Oct 11, 2018)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
PreventionGenetics, part of Exact Sciences
Accession: SCV000852808.1
First in ClinVar: Nov 20, 2018 Last updated: Nov 20, 2018 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Uncertain significance
(Jan 12, 2018)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Malignant hyperthermia, susceptibility to, 1 |
Illumina Laboratory Services, Illumina
Accession: SCV001287278.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
show
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Uncertain significance
(Jan 12, 2018)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Central core myopathy |
Illumina Laboratory Services, Illumina
Accession: SCV001287279.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
show
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Observation:
2
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 2
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Uncertain significance
(Jan 12, 2018)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Congenital multicore myopathy with external ophthalmoplegia |
Illumina Laboratory Services, Illumina
Accession: SCV001287280.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
show
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Uncertain significance
(Oct 08, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Central core myopathy
Malignant hyperthermia, susceptibility to, 1 Congenital myopathy 4A, autosomal dominant Congenital multicore myopathy with external ophthalmoplegia King Denborough syndrome |
Fulgent Genetics, Fulgent Genetics
Accession: SCV002786158.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
Uncertain significance
(Nov 01, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
RYR1-related disorder |
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001416681.3
First in ClinVar: Jul 16, 2020 Last updated: Feb 07, 2023 |
Comment:
show
This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 2627 of the RYR1 protein (p.Val2627Gly). This variant is present in population databases (no rsID available, gnomAD 0.02%). 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: 590599). 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 expected to disrupt RYR1 protein function. 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)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Uncertain Significance
(Aug 06, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Malignant hyperthermia, susceptibility to, 1
(Autosomal dominant inheritance)
|
All of Us Research Program, National Institutes of Health
Accession: SCV004832922.2
First in ClinVar: Apr 20, 2024 Last updated: Dec 14, 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:
show
This missense variant replaces valine with glycine at codon 2627 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 been reported in an individual affected with malignant hyperthermia susceptibility (PMID: 23460944). This variant has been identified in 13/249716 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant occurring at the same codon, c.7879G>C (p.Val2627Leu), is a known pathogenic mutation (ClinVar Variation ID: 1321038), suggesting that Val at this position is important for RYR1 protein function. 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)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Number of individuals with the variant: 14
Zygosity: Single Heterozygote
|
|
|
Uncertain significance
(Nov 19, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not specified |
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005726177.1
First in ClinVar: Feb 16, 2025 Last updated: Feb 16, 2025 |
Comment:
show
Variant summary: RYR1 c.7880T>G (p.Val2627Gly) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 249716 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in RYR1 causing Malignant Hyperthermia Susceptibility (5.2e-05 vs 8.8e-05), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.7880T>G in individuals affected with verified Malignant Hyperthermia Susceptibility and no experimental evidence demonstrating its impact on protein function have been reported. The following publications have been ascertained in the context of this evaluation (PMID: 35697689, 23460944, 35285867). ClinVar contains an entry for this variant (Variation ID: 590599). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Uncertain significance
(Jan 08, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Long QT syndrome |
Dept of Medical Biology, Uskudar University
Accession: SCV004021957.3
First in ClinVar: Jul 29, 2023 Last updated: Apr 13, 2025 |
Observation 1
Collection method: research
Allele origin: paternal
Affected status: yes
Number of individuals with the variant: 1
Sex: female
Ethnicity/Population group: Turkish
Geographic origin: Turkey
|
|
|
Uncertain significance
(Nov 20, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Congenital multicore myopathy with external ophthalmoplegia
(Autosomal recessive inheritance)
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV004175937.2
First in ClinVar: Dec 17, 2023 Last updated: Apr 13, 2025 |
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
Clinical Features:
Microcephaly (present) , Developmental regression (present) , Severe global developmental delay (present) , Hypotonia (present)
Sex: male
|
|
|
Uncertain significance
(May 23, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Revvity Omics, Revvity
Accession: SCV004236902.2
First in ClinVar: Feb 04, 2024 Last updated: Sep 06, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
Comment:
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Comment:
This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 2627 of the RYR1 protein (p.Val2627Gly). This variant is present in population databases (no rsID available, gnomAD 0.02%). 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: 590599). 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 expected to disrupt RYR1 protein function. 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 valine with glycine at codon 2627 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 been reported in an individual affected with malignant hyperthermia susceptibility (PMID: 23460944). This variant has been identified in 13/249716 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant occurring at the same codon, c.7879G>C (p.Val2627Leu), is a known pathogenic mutation (ClinVar Variation ID: 1321038), suggesting that Val at this position is important for RYR1 protein function. 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.
Comment:
Variant summary: RYR1 c.7880T>G (p.Val2627Gly) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 249716 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in RYR1 causing Malignant Hyperthermia Susceptibility (5.2e-05 vs 8.8e-05), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.7880T>G in individuals affected with verified Malignant Hyperthermia Susceptibility and no experimental evidence demonstrating its impact on protein function have been reported. The following publications have been ascertained in the context of this evaluation (PMID: 35697689, 23460944, 35285867). ClinVar contains an entry for this variant (Variation ID: 590599). Based on the evidence outlined above, the variant was classified as uncertain significance.
Comment:
Criteria: PM2, PM5, PP3
Comment:
Criteria applied: PS4_MOD,PM2_SUP,PP3
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Variants in ASPH cause exertional heat illness and are associated with malignant hyperthermia susceptibility. | Endo Y | Nature communications | 2022 | PMID: 35697689 |
| Referral Indications for Malignant Hyperthermia Susceptibility Diagnostics in Patients without Adverse Anesthetic Events in the Era of Next-generation Sequencing. | van den Bersselaar LR | Anesthesiology | 2022 | PMID: 35285867 |
| CASQ1 gene is an unlikely candidate for malignant hyperthermia susceptibility in the North American population. | Kraeva N | Anesthesiology | 2013 | PMID: 23460944 |
Text-mined citations for rs747337318 ...
HelpThese 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 Sep 07, 2025
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.