ClinVar Genomic variation as it relates to human health
NM_001256071.3(RNF213):c.14429G>A (p.Arg4810Lys)
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.
Pathogenic(4); Likely pathogenic(1); Uncertain significance(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001256071.3(RNF213):c.14429G>A (p.Arg4810Lys)
Variation ID: 39700 Accession: VCV000039700.35
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q25.3 17: 80385145 (GRCh38) [ NCBI UCSC ] 17: 78358945 (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 Apr 4, 2013 Apr 15, 2024 Jan 4, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001256071.3:c.14429G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001243000.2:p.Arg4810Lys missense NC_000017.11:g.80385145G>A NC_000017.10:g.78358945G>A NG_031980.2:g.129285G>A - Protein change
- R4810K
- Other names
- R4859K
- NM_020914.4:c.14576G>A
- p.Arg4810Lys
- Canonical SPDI
- NC_000017.11:80385144:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- Unknown function
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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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0.00120 (A)
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00006
1000 Genomes Project 30x 0.00109
1000 Genomes Project 0.00120
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
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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
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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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RNF213 | - | - |
GRCh38 GRCh37 |
410 | 711 | |
RNF213-AS1 | - | - | - | GRCh38 | - | 279 |
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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
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Jul 26, 2022 | RCV000032902.10 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jan 4, 2024 | RCV001531872.23 |
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
(Jan 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Moyamoya disease 2
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002058596.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000039700, 3billion dataset, PS1_S). … (more)
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000039700, 3billion dataset, PS1_S). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000240, PM2_M). The carrying of p. Arg4810Lys in RNF213 gene is closely related the MoyaMoya disease risk in an east asian (PMID 21799892, 25278557). In silico tool predictions suggest no damaging effect of the variant on gene or gene product (REVEL:0.071<=0.4, 3CNET:0.018<=0.252, BP4_P). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Stroke disorder (present)
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Uncertain significance
(Apr 03, 2023)
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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: SCV001830948.2
First in ClinVar: Sep 08, 2021 Last updated: Apr 09, 2023 |
Comment:
Also known as c.14576G>A or R4859K due to alternate nomenclature; The most common variant identified in the RNF213 gene in individuals of East Asian background … (more)
Also known as c.14576G>A or R4859K due to alternate nomenclature; The most common variant identified in the RNF213 gene in individuals of East Asian background and has been reported numerous times to confer susceptibility to moyamoya disease (Liu et al., 2011; Kamada et al., 2011; Miyatake et al., 2012; Zhang et al., 2016); Homozygosity has been associated with earlier age of onset of disease compared to heterozygous individuals (Miyatake et al., 2012); Functional studies indicate that cells overexpressing R4810K have mitotic abnormalities and decreased angiogenesis, and a transgenic murine model showed that the R4810K variant inhibits angiogenesis in mice (Hitomi et al., 2013a; Hitomi et al., 2013b; Kobayashi et al., 2015); Other functional studies have shown that R4810K may not affect transcription levels or ubiquitination activity, and a knock-in murine model showed that mice harboring R4810K grew normally with no significant differences from wild type mice and no spontaneous development of moyamoya disease (Liu et al., 2011; Kanoke et al., 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23110205, 25547042, 24029639, 26292667, 26530418, 25876583, 27375007, 25964206, 22878964, 25883833, 28414759, 29165161, 30925911, 33356381, 23850618, 23994138, 22931863, 22377813, 22688066, 25278557, 23970789, 21048783, 25817623, 26126547, 26315378, 26590131, 26125557, 26806063, 27253870, 27128593, 21799892, 28063898, 28506590, 28617845, 29500468, 28962888, 27365075, 27476341, 31060437, 29718794, 30922903, 30615506, 30562119, 30276334, 30992731, 31293503, 29567577, 31197213, 30947170, 31347299, 31542298, 34013582, 31589614, 32434013, 34680863, 34749017, 34624841, 34716882, 35876407, 34335228, 36936868, 36324634, 32212963, 35231114, 34710878, 31908915, 35455046, 32088313, 32814565, 35701560, 35642380, 31818681, 31733606, 31949090, 32073714, 32369273, 32438004, 28931766, 33482763, 33055470, 33175469, 28619492, 32572006, 32686731, 33370357) (less)
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Pathogenic
(Jul 26, 2022)
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criteria provided, single submitter
Method: clinical testing
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Moyamoya disease 2
Affected status: unknown
Allele origin:
germline
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Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV002495932.2
First in ClinVar: Apr 08, 2022 Last updated: May 06, 2023 |
Comment:
RNF213 NM_001256071.2 exon 60 p.Arg4810Lys (c.14429G>A): This variant was first identified as a founder variant common in East Asian patients with Moyamoyma disease (MMD) (Liu … (more)
RNF213 NM_001256071.2 exon 60 p.Arg4810Lys (c.14429G>A): This variant was first identified as a founder variant common in East Asian patients with Moyamoyma disease (MMD) (Liu 2011 PMID: 21799892, Kamada 2011 PMID: 21048783). It has since been reported in the literature in numerous individuals with MMD in both the heterozygous and homozygous state, segregating with disease in several affected family members (Selected publications: Liu 2011 PMID:21799892, Miyatake 2012 PMID:22377813, Hitomi 2013 PMID:23850618, Cecchi 2014 PMID:25278557, Zhang 2017 PMID: 28063898, Zhang 2019 PMID:31290353). However, multiple unaffected family members have also been reported who carry this variant (Liu 2011 PMID: 21799892, Cecchi 2014 PMID:25278557), and it is present in 0.02% (32/143300) of all alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/17-80385145-G-A?dataset=gnomad_r3). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. Given the prevalence of this variant in unaffected and affected individuals with MMD, the odds ratio of this variant has been estimated to be 112 in East Asian populations (Liu 2011 PMID: 21799892). Functional studies have shown a deleterious effect of this variant, but these studies have not been replicated with in vivo mouse models (Hitomi 2013 PMID:23850618, Kanoke 2015 PMID: 26315378, Kobayashi 2015 PMID:26126547). However, these studies may not accurately represent in vivo biological function in humans. Evolutionary conservation suggests that this variant may not impact the protein, while computational predictive tools for this variant are unclear. This variant is also documented in ClinVar (Variation ID:39700). In summary, this variant is classified as a pathogenic risk allele given extensive published case-control data which suggests the involvement of other genetic and/or environmental factors. (less)
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Pathogenic
(Apr 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001747183.14
First in ClinVar: Jul 10, 2021 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Moyamoya disease 2
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001140846.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Uncertain significance
(Jan 24, 2022)
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criteria provided, single submitter
Method: clinical testing
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Moyamoya disease 2
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV002573549.1
First in ClinVar: Sep 24, 2022 Last updated: Sep 24, 2022 |
Comment:
Heterozygous missense variation in exon 61 of the RNF213 gene that result in the amino acid substitution of lysine for arginine at codon 4859 was … (more)
Heterozygous missense variation in exon 61 of the RNF213 gene that result in the amino acid substitution of lysine for arginine at codon 4859 was detected. The observed variant has previously been reported in patient affected with Moyamoya disease and it lies in the glycosyl hydrolase family 20, catalytic domain of RNF213 protein. The p.Arg4859Lys variant has minor allele frequency of 0.1% and 0.02% in the 1000 genome and gnomAD database. In summary, the variant meets our criteria to be classified as variant of uncertain significance. (less)
Age: 30-39 years
Sex: female
Method: DNA was used to perform targeted gene capture using a custom capture kit. Libraries were sequenced to mean >80-100X coverage on Illumina sequencing platform. Sequence obtained were aligned to human references genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted genes relevant to clinical indication
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Pathogenic
(Jan 04, 2024)
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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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Invitae
Accession: SCV002281428.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 4810 of the RNF213 protein (p.Arg4810Lys). … (more)
This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 4810 of the RNF213 protein (p.Arg4810Lys). This variant is present in population databases (rs112735431, gnomAD 0.3%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individuals with autosomal dominant and recessive Moyamoya disease (PMID: 21048783, 21799892, 22377813, 22931863, 23110205). It is commonly reported in individuals of East Asian ancestry (PMID: 21799892, 26530418). ClinVar contains an entry for this variant (Variation ID: 39700). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The lysine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on RNF213 function (PMID: 21799892, 26126547). For these reasons, this variant has been classified as Pathogenic. (less)
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risk factor
(Dec 01, 2012)
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no assertion criteria provided
Method: literature only
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MOYAMOYA DISEASE 2, SUSCEPTIBILITY TO
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000045349.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 21, 2021 |
Comment on evidence:
In Japanese patients with moyamoya disease (MYMY2; 607151), Kamada et al. (2011) found a significant association between disease and a c.14576G-A transition (c.14576G-A, NM_020914.4) in … (more)
In Japanese patients with moyamoya disease (MYMY2; 607151), Kamada et al. (2011) found a significant association between disease and a c.14576G-A transition (c.14576G-A, NM_020914.4) in exon 60 of the RNF213 gene, resulting in an arg4859-to-lys (R4859K) substitution. In 19 of 20 families, heterozygosity for the variant was found in 39 (92.9%) of 41 patients with the disorder and in 13 (46.4%) of 28 family members without the disorder. Three (7.1%) patients had the variant in the homozygous state. The overall p value among familial cases was 4.2 x 10(-7). None of 15 family members without the variant developed the disease. The variant was also present in heterozygosity and homozygosity in 45 (71.4%) and 1 (1.6%) of 63 Japanese patients with sporadic disease, respectively, and in 6 (1.4%) of 429 controls. There was no phenotypic difference between homozygous and heterozygous carriers. Overall, carrying the variant conferred an odds ratio of 190.8 for development of the disorder (p = 1.2 x 10(-43)). The R4859K variant was not found in 400 Caucasian controls. Miyatake et al. (2012) found the c.14576G-A transition in 39 (95.1%) of 41 Japanese patients with familial moyamoya disease, in 129 (79.2%) of 163 Japanese patients with sporadic moyamoya disease, and in 5 (1.8%) of 283 Japanese control individuals. Fifteen of the 168 patients with the variant carried it in the homozygous state, whereas all 5 controls carried it in the heterozygous state. Most patients inherited the allele from either or both unaffected parents; all parents were heterozygous for the variant. Miyatake et al. (2012) concluded that heterozygosity for the 14576G-A variant confers an odds ratio of 236 for development of the disorder. Patients with the 14576G-A variant had an earlier age at onset (as early as age 4 years) and tended to have a higher frequency of infarcts, posterior cerebral artery involvement, bilateral involvement, seizures, and intellectual impairment compared to patients without the variant. However, heterozygosity for the variant was also found in adult patients. Comparisons of clinical features between 5 parent-offspring pairs who were heterozygous for the variant showed anticipation. Miyatake et al. (2012) reported a Japanese brother and sister with moyamoya disease who were heterozygous and homozygous for the c.14576G-A mutation, respectively. The homozygous brother had onset of recurrent strokes in early childhood, with deterioration in cognitive function and residual symptoms, including paresis, headache, and visual loss, whereas the heterozygous sister had only 1 stroke at age 17 years and no residual symptoms. Brain imaging showed more severe vascular occlusion in the homozygous brother. The findings suggested a dosage effect for this variant. In affected members of 41 Japanese families and 1 Korean family with moyamoya disease, Liu et al. (2011) identified a G-to-A transition in the RNF213 gene, resulting in an arg4810-to-lys (R4810K) substitution (ss179362673) at a conserved residue. The variant segregated with the disorder, although some carriers of the variant did not have moyamoya disease, indicating incomplete penetrance. The mutation was initially found by linkage analysis followed by exome sequencing in eight 3-generation families. Haplotype analysis indicated a founder effect. A case-control study of 251 East Asian patients and 707 controls showed a significant association between R4810K and the disorder (odds ratio of 111.8, p = 10 x 10(-19)). The variant was found in about 1% of controls in East Asian populations, and some Japanese controls were homozygous for the variant, arguing against a gene dosage effect. Although R4810K was identified in 3 populations, the population attributable risks in the Japanese (145/161; 90%) and Korean (30/38; 79%) populations were larger than that in the Chinese population (12/52; 23%). In addition, R4810K was not present among Caucasian cases or controls. In vitro functional expression studies in HEK293 cells showed that the R4810K protein was expressed and localized normally within the cell; the variant protein also had normal ubiquitin activity. Knockout of the homologs in zebrafish caused abnormal vascular development, including abnormal sprouting vessels particularly in the head region. Liu et al. (2011) postulated that variation in the RNF213 gene acts with environmental factors to result in moyamoya disease. Liu et al. (2011) stated that the mutation was found in the short isoform of RNF213, based on AB537889. Huang et al. (2016) found evidence of the association of the c.14576G-A polymorphism (rs112735431) in the RNF213 gene with the risk of moyamoya disease in Asian populations. In a case-control study of 81 Chinese MYMY patients and 100 healthy controls, the A allele frequency was significantly higher in the MYMY group than in the control group (OR = 9.37, 95% CI = 2.10-41.84, p less than 0.001). In a metaanalysis of 8 case-control studies in Asian populations, including 985 patients and 2,335 controls, the A allele was significantly associated with risk of MYMY (dominant model: OR = 74.55, 95% CI = 35.86-154.98, p = 0.00001). The risk was greater in the Japanese and Korean populations than in the Chinese population studied. (less)
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Likely pathogenic
(Sep 08, 2014)
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no assertion criteria provided
Method: research
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Moyamoya disease 2
Affected status: yes
Allele origin:
germline
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Department of Internal Medicine, University of Texas Health Science Center at Houston
Additional submitter:
University of Washington Center for Mendelian Genomics, University of Washington
Accession: SCV000246198.1
First in ClinVar: Sep 29, 2015 Last updated: Sep 29, 2015 |
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Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Unknown function
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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV002573549.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Association between the rs112735431 polymorphism of the RNF213 gene and moyamoya disease: A case-control study and meta-analysis. | Huang Y | Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia | 2016 | PMID: 27515544 |
Disease Variant Landscape of a Large Multiethnic Population of Moyamoya Patients by Exome Sequencing. | Shoemaker LD | G3 (Bethesda, Md.) | 2015 | PMID: 26530418 |
Biochemical and Functional Characterization of RNF213 (Mysterin) R4810K, a Susceptibility Mutation of Moyamoya Disease, in Angiogenesis In Vitro and In Vivo. | Kobayashi H | Journal of the American Heart Association | 2015 | PMID: 26126547 |
RNF213 rare variants in an ethnically diverse population with Moyamoya disease. | Cecchi AC | Stroke | 2014 | PMID: 25278557 |
Molecular analysis of RNF213 gene for moyamoya disease in the Chinese Han population. | Wu Z | PloS one | 2012 | PMID: 23110205 |
Sibling cases of moyamoya disease having homozygous and heterozygous c.14576G>A variant in RNF213 showed varying clinical course and severity. | Miyatake S | Journal of human genetics | 2012 | PMID: 22931863 |
Homozygous c.14576G>A variant of RNF213 predicts early-onset and severe form of moyamoya disease. | Miyatake S | Neurology | 2012 | PMID: 22377813 |
Identification of RNF213 as a susceptibility gene for moyamoya disease and its possible role in vascular development. | Liu W | PloS one | 2011 | PMID: 21799892 |
A genome-wide association study identifies RNF213 as the first Moyamoya disease gene. | Kamada F | Journal of human genetics | 2011 | PMID: 21048783 |
Text-mined citations for rs112735431 ...
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.