VCV000582126.9 - ClinVar

NM_000540.3(RYR1):c.14690G>A (p.Gly4897Asp)

Germline

Classification

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.

(3)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Likely pathogenic(2); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000540.3(RYR1):c.14690G>A (p.Gly4897Asp)

Variation ID: 582126 Accession: VCV000582126.9

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19q13.2 19: 38584986 (GRCh38) [ NCBI UCSC ] 19: 39075626 (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	Oct 10, 2018	May 1, 2024	Jun 26, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000540.3:c.14690G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000531.2:p.Gly4897Asp	missense
NM_001042723.2:c.14675G>A	NP_001036188.1:p.Gly4892Asp	missense
NC_000019.10:g.38584986G>A
NC_000019.9:g.39075626G>A
NG_008866.1:g.156287G>A
LRG_766:g.156287G>A
LRG_766t1:c.14690G>A	LRG_766p1:p.Gly4897Asp

... more HGVS ... less HGVS

Protein change

G4897D, G4892D

Other names

Canonical SPDI

NC_000019.10:38584985:G: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.

Links

dbSNP: rs118192148 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	8927	9242

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.
RYR1-related disorder	Likely pathogenic (1)	criteria provided, single submitter	Oct 24, 2017	RCV000706118.7
not provided	Likely pathogenic (1)	criteria provided, single submitter	Aug 17, 2018	RCV000721396.5
Inborn genetic diseases	Uncertain significance (1)	criteria provided, single submitter	Jun 26, 2023	RCV003352998.2

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.
Likely pathogenic (Aug 17, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000852450.1 First in ClinVar: Nov 20, 2018 Last updated: Nov 20, 2018
Likely pathogenic (Oct 24, 2017)	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: SCV000835150.4 First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 28492532‚ 17226826‚ 16084090‚ 23919265‚ 24561095 Comment: 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 … (more) 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. (less)
Uncertain significance (Jun 26, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV004076520.2 First in ClinVar: Oct 28, 2023 Last updated: May 01, 2024	Publications: PubMed (8) PubMed: 10097041‚ 23308296‚ 24561095‚ 25517095‚ 27573175‚ 32236737‚ 35428369‚ 35627144 Comment: 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 … (more) 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. (less)

Comment:

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.

Comment:

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.

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
Central Core Disease: Facial Weakness Differentiating Biallelic from Monoallelic Forms.	Cotta A	Genes	2022	PMID: 35627144
Expanding the clinical-pathological and genetic spectrum of RYR1-related congenital myopathies with cores and minicores: an Italian population study.	Fusto A	Acta neuropathologica communications	2022	PMID: 35428369
Intracellular calcium leak as a therapeutic target for RYR1-related myopathies.	Kushnir A	Acta neuropathologica	2020	PMID: 32236737
Structural insights into Ca(2+)-activated long-range allosteric channel gating of RyR1.	Wei R	Cell research	2016	PMID: 27573175
Structure of the rabbit ryanodine receptor RyR1 at near-atomic resolution.	Yan Z	Nature	2015	PMID: 25517095
Novel RYR1 missense mutations in six Chinese patients with central core disease.	Gu M	Neuroscience letters	2014	PMID: 24561095
Genotype-phenotype correlations in recessive RYR1-related myopathies.	Amburgey K	Orphanet journal of rare diseases	2013	PMID: 23919265
Ca2+ release in muscle fibers expressing R4892W and G4896V type 1 ryanodine receptor disease mutants.	Lefebvre R	PloS one	2013	PMID: 23308296
Central core disease due to recessive mutations in RYR1 gene: is it more common than described?	Kossugue PM	Muscle & nerve	2007	PMID: 17226826
Ryanodine receptor 1 mutations, dysregulation of calcium homeostasis and neuromuscular disorders.	Treves S	Neuromuscular disorders : NMD	2005	PMID: 16084090
Luminal loop of the ryanodine receptor: a pore-forming segment?	Balshaw D	Proceedings of the National Academy of Sciences of the United States of America	1999	PMID: 10097041
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Text-mined citations for rs118192148 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000540.3(RYR1):c.14690G>A (p.Gly4897Asp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs118192148 ...