Submissions for variant NM_001256071.3(RNF213):c.14429G>A (p.Arg4810Lys)

gnomAD frequency: 0.00004  dbSNP: rs112735431

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mendelics	RCV000032902	SCV001140846	pathogenic	Moyamoya disease 2	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001531872	SCV001747183	pathogenic	not provided	2021-04-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001531872	SCV001830948	pathogenic	not provided	2024-07-18	criteria provided, single submitter	clinical testing	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 (PMID: 23994138, 23850618, 26126547); 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 (PMID: 26315378, 21799892); In silico analysis indicates that this missense variant does not alter protein structure/function; Also known as c.14576G>A or R4859K due to alternate nomenclature; This variant is associated with the following publications: (PMID: 23110205, 25547042, 24029639, 26292667, 26530418, 25876583, 27375007, 25964206, 22878964, 25883833, 28414759, 29165161, 30925911, 33356381, 23850618, 22931863, 22377813, 22688066, 23970789, 21048783, 25817623, 26126547, 26590131, 26125557, 26806063, 27253870, 28063898, 28506590, 28617845, 29500468, 28962888, 27365075, 27476341, 31060437, 29718794, 30922903, 30615506, 30562119, 30276334, 30992731, 31293503, 29567577, 31197213, 30947170, 31347299, 31542298, 34013582, 31589614, 35640559, 36657715, 36063804, 38115307, 37768541, 37657303, 36916017, 37554039, 36147931, 37722316, 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, 37137523, 35861108, 37269436, 21799892, 25278557, 23994138, 26315378, 37012328, 38927660, 27128593)
3billion	RCV000032902	SCV002058596	likely pathogenic	Moyamoya disease 2	2022-01-03	criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001531872	SCV002281428	pathogenic	not provided	2024-01-04	criteria provided, single submitter	clinical testing	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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000032902	SCV002495932	pathogenic	Moyamoya disease 2	2022-07-26	criteria provided, single submitter	clinical testing	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.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000032902	SCV002573549	uncertain significance	Moyamoya disease 2	2024-10-26	criteria provided, single submitter	clinical testing	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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000032902	SCV005400249	pathogenic	Moyamoya disease 2	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. However, gain of function and dominant negative have been reported (PMIDs: 26662949, 35135845). (I) 0108 - This gene is associated with susceptibility to moyamoya disease 2 (MIM#607151), with both recessive and dominant inheritance patterns have been reported, where recessive inheritance has earlier onset of symptoms (PMID: 26198278). (I) 0112 - The condition associated with this gene has incomplete penetrance. Low penetrance is well reported for the p.(Arg4810Lys) variant in this gene (PMID: 35605621). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to lysine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2 and v3: 104 heterozygotes, 1 homozygote). (SP) 0309 - Alternative amino acid changes at the same position have been observed in gnomAD (v2) (highest allele count: 10 heterozygotes, 0 homozygotes). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been well-reported as an east Asian founder variant associated with moyamoya disease, however its penetrance is low (1 in 150) (PMIDs: 35605621, 35401401). It has been reported as heterozygous in many individuals with moyamoya disease, as homozygous in affected individuals with earlier ages of onset, and also as heterozygous in unaffected individuals (PMIDs: 35876407, 22377813). (SP) 1010 - Functional evidence for this variant is inconclusive. Functional studies using HeLa cells with this variant had wild type level of ATPase activity and retained oligomerisation activity, however they had a reduced autoubiquitylation activity (PMID: 35135845). Another study of the mouse isoform showed this variant did not affect poly-ubiquitination activity (PMID: 32573437). (I) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Mayo Clinic Laboratories, Mayo Clinic	RCV001531872	SCV005413284	pathogenic	not provided	2024-06-25	criteria provided, single submitter	clinical testing	BP4, PS3_supporting, PS4
OMIM	RCV000032902	SCV000045349	risk factor	Moyamoya disease 2	2012-12-01	no assertion criteria provided	literature only
Department of Internal Medicine, University of Texas Health Science Center at Houston	RCV000032902	SCV000246198	likely pathogenic	Moyamoya disease 2	2014-09-08	no assertion criteria provided	research