ClinVar Genomic variation as it relates to human health
NM_000540.3(RYR1):c.325C>T (p.Arg109Trp)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000540.3(RYR1):c.325C>T (p.Arg109Trp)
Variation ID: 12988 Accession: VCV000012988.47
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19q13.2 19: 38443612 (GRCh38) [ NCBI UCSC ] 19: 38934252 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Jun 9, 2014 Apr 15, 2024 Mar 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000540.3:c.325C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000531.2:p.Arg109Trp missense NM_001042723.2:c.325C>T NP_001036188.1:p.Arg109Trp missense NC_000019.10:g.38443612C>T NC_000019.9:g.38934252C>T NG_008866.1:g.14913C>T LRG_766:g.14913C>T LRG_766t1:c.325C>T LRG_766p1:p.Arg109Trp P21817:p.Arg109Trp - Protein change
- R109W
- Other names
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- Canonical SPDI
- NC_000019.10:38443611:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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0.00020 (T)
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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD) 0.00005
The Genome Aggregation Database (gnomAD), exomes 0.00008
Exome Aggregation Consortium (ExAC) 0.00011
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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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. |
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RYR1 | No evidence available | No evidence available |
GRCh38 GRCh37 |
7832 | 8114 |
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. |
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Pathogenic (1) |
no assertion criteria provided
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Dec 27, 2005 | RCV000013860.27 | |
Pathogenic/Likely pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Dec 15, 2023 | RCV000119608.33 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 22, 2023 | RCV000655512.10 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Nov 19, 2019 | RCV001199051.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 22, 2021 | RCV002496350.2 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Mar 29, 2024 | RCV003447473.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 31, 2023 | RCV003891435.1 |
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. |
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Likely pathogenic
(Nov 07, 2013)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal unknown)
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000194822.1
First in ClinVar: Nov 23, 2014 Last updated: Nov 23, 2014 |
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Likely pathogenic
(Jan 03, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001450338.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 1
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Pathogenic
(Nov 22, 2021)
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criteria provided, single submitter
Method: clinical testing
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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
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002807461.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Sep 27, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001983919.3
First in ClinVar: Oct 30, 2021 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect: R109W expressed in the homozygous state results in complete loss of calcium conductance (Zhou et al., 2006); Not … (more)
Published functional studies demonstrate a damaging effect: R109W expressed in the homozygous state results in complete loss of calcium conductance (Zhou et al., 2006); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29298851, 23553787, 17483490, 17365175, 18171678, 27858727, 28818389, 28357410, 16380615, 30155738, 30611313, 31127727, 33646172, 33646171, 32381029, 17033962, 34463354, 31589614, 32528171, 35361824, 27535533, 23826317, 24195946, 28547000, 22473935, 27855725, 23069638, 16084090, 33333461, 33726816, 16940308) (less)
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Likely pathogenic
(Apr 08, 2022)
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criteria provided, single submitter
Method: clinical testing
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Central core myopathy
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004175376.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
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Pathogenic
(Dec 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002019944.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Dec 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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RYR1-Related Disorders
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000777443.8
First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 109 of the RYR1 protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 109 of the RYR1 protein (p.Arg109Trp). This variant is present in population databases (rs118192173, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal recessive congenital myopathy (PMID: 23826317, 28357410; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12988). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR1 protein function. Experimental studies have shown that this missense change affects RYR1 function (PMID: 18171678). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 31, 2023)
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criteria provided, single submitter
Method: clinical testing
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RYR1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV000852564.2
First in ClinVar: Nov 23, 2014 Last updated: Mar 16, 2024 |
Comment:
The RYR1 c.325C>T variant is predicted to result in the amino acid substitution p.Arg109Trp. This variant has been reported in individuals with autosomal recessive core … (more)
The RYR1 c.325C>T variant is predicted to result in the amino acid substitution p.Arg109Trp. This variant has been reported in individuals with autosomal recessive core myopathy (Zhou et al. 2006. PubMed ID: 16940308; Abath Neto et al. 2017. PubMed ID: 28818389; Matthews et al. 2018. PubMed ID: 29298851; Table S1, Natera-de Benito et al. 2020. PubMed ID: 33333461). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant has been classified as pathogenic or likely pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/12988/). This variant is interpreted as pathogenic. (less)
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Pathogenic
(Sep 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001248774.20
First in ClinVar: May 12, 2020 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 2
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Likely pathogenic
(Nov 19, 2019)
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criteria provided, single submitter
Method: clinical testing
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Congenital myopathy 4A, autosomal dominant
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001370046.2
First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020 |
Comment:
This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3.
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Likely pathogenic
(May 26, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: yes
Allele origin:
germline
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AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002501075.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
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Pathogenic
(Mar 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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Central core myopathy
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004807515.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
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Pathogenic
(Dec 27, 2005)
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no assertion criteria provided
Method: literature only
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MINICORE MYOPATHY WITH EXTERNAL OPHTHALMOPLEGIA
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000034107.2
First in ClinVar: Apr 04, 2013 Last updated: Sep 04, 2016 |
Comment on evidence:
In 2 sibs with minicore myopathy with external ophthalmoplegia (255320), Jungbluth et al. (2005) identified a 325C-T transition in exon 4 of the RYR1 gene, … (more)
In 2 sibs with minicore myopathy with external ophthalmoplegia (255320), Jungbluth et al. (2005) identified a 325C-T transition in exon 4 of the RYR1 gene, resulting in an arg109-to-trp (R109W) substitution in a highly conserved region. Analysis of cDNA showed homozygosity for the mutation, but genomic DNA showed heterozygosity. Jungbluth et al. (2005) postulated that the second allele was either not expressed or deleted and may indicate a promoter mutation or a large deletion. Haplotype analysis and the unaffected parental carrier status were consistent with biallelic mutations and autosomal recessive inheritance. (less)
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not provided
(-)
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no classification provided
Method: not provided
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not provided
Affected status: not provided
Allele origin:
unknown
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Leiden Muscular Dystrophy (RYR1)
Accession: SCV000154515.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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The Phenotype and Genotype of Congenital Myopathies Based on a Large Pediatric Cohort. | Natera-de Benito D | Pediatric neurology | 2021 | PMID: 33333461 |
Sequential targeted exome sequencing of 1001 patients affected by unexplained limb-girdle weakness. | Töpf A | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 32528171 |
Panel-Based Exome Sequencing for Neuromuscular Disorders as a Diagnostic Service. | Westra D | Journal of neuromuscular diseases | 2019 | PMID: 31127727 |
'Dusty core disease' (DuCD): expanding morphological spectrum of RYR1 recessive myopathies. | Garibaldi M | Acta neuropathologica communications | 2019 | PMID: 30611313 |
Atypical periodic paralysis and myalgia: A novel RYR1 phenotype. | Matthews E | Neurology | 2018 | PMID: 29298851 |
Common and variable clinical, histological, and imaging findings of recessive RYR1-related centronuclear myopathy patients. | Abath Neto O | Neuromuscular disorders : NMD | 2017 | PMID: 28818389 |
Phenotypes, genotypes, and prevalence of congenital myopathies older than 5 years in Denmark. | Witting N | Neurology. Genetics | 2017 | PMID: 28357410 |
An integrated diagnosis strategy for congenital myopathies. | Böhm J | PloS one | 2013 | PMID: 23826317 |
RyR1 deficiency in congenital myopathies disrupts excitation-contraction coupling. | Zhou H | Human mutation | 2013 | PMID: 23553787 |
Single channel properties of heterotetrameric mutant RyR1 ion channels linked to core myopathies. | Xu L | The Journal of biological chemistry | 2008 | PMID: 18171678 |
Epigenetic allele silencing unveils recessive RYR1 mutations in core myopathies. | Zhou H | American journal of human genetics | 2006 | PMID: 17033962 |
Characterization of recessive RYR1 mutations in core myopathies. | Zhou H | Human molecular genetics | 2006 | PMID: 16940308 |
Minicore myopathy with ophthalmoplegia caused by mutations in the ryanodine receptor type 1 gene. | Jungbluth H | Neurology | 2005 | PMID: 16380615 |
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Text-mined citations for rs118192173 ...
HelpRecord last updated Apr 15, 2024
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.