ClinVar Miner

Submissions for variant NM_031407.7(HUWE1):c.12559C>T (p.Arg4187Cys)

gnomAD frequency: 0.00002  dbSNP: rs121918527
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Center for Human Genetics Tuebingen RCV000585168 SCV000693336 likely pathogenic not provided 2017-07-01 criteria provided, single submitter clinical testing
GeneDx RCV000585168 SCV001981914 pathogenic not provided 2023-05-16 criteria provided, single submitter clinical testing Identified in multiple male family members with intellectual disability in published literature (Froyen et al., 2008); Published functional studies demonstrate a damaging effect on protein function (Opperman et al., 2017: Hunkeler et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19377476, 23871722, 29180823, 29307790, 27130160, 29118367, 18252223, 33948573, 32336296, 34314700, 28445732, 36111624, 37167062)
Invitae RCV000585168 SCV002187438 uncertain significance not provided 2021-07-15 criteria provided, single submitter clinical testing This variant is not present in population databases (ExAC no frequency). 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. Experimental studies have shown that this variant affects HUWE1 protein function (PMID: 29118367). 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 HUWE1 protein function. ClinVar contains an entry for this variant (Variation ID: 10678). This variant is also known as c.12229C>T (p.R4077C). This variant has been observed in individual(s) with intellectual disability (PMID: 18252223, 19377476). This sequence change replaces arginine with cysteine at codon 4187 of the HUWE1 protein (p.Arg4187Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV002470707 SCV002767558 pathogenic Non-syndromic X-linked intellectual disability 2020-05-25 criteria provided, single submitter clinical testing A hemizygous missense variant was identified, NM_031407.6(HUWE1):c.12559C>T in exon 81 of 84 of the HUWE1 gene. This substitution is predicted to create a major amino acid change from an arginine to a cysteine at position 4187 of the protein, NP_113584.3(HUWE1):p.(Arg4187Cys). The arginine at this position has very high conservation (100 vertebrates, UCSC), and is located within the HECT domain. In silico software predicts this variant to be damaging (Polyphen, SIFT, CADD, Mutation Taster) and the variant is not present in the gnomAD population database. It has been previously reported in patients with X-linked intellectual disability (ClinVar; Hu, H. et al. (2016)). It has also been shown to segregate with disease in one family (Froyen, G. et al. (2008)). In addition, functional studies showed decreased DNA repair capacity and hypersensitivity to oxidative stress in patient lymphoblastoid cells (Bosshard, M. et al. (2017)). A different variant in the same codon resulting in a change to a histidine has been reported as likely pathogenic (ClinVar; Niranjan, T. et al . (2015)). Based on information available at the time of curation, this variant has been classified as PATHOGENIC.
Institute of Human Genetics, University of Leipzig Medical Center RCV000011424 SCV004242465 likely pathogenic Intellectual disability, X-linked syndromic, Turner type 2023-12-14 criteria provided, single submitter clinical testing Criteria applied: PS4_MOD,PM5,PS3_SUP,PM2_SUP,PP1,PP2
Molecular Genetics Lab, CHRU Brest RCV000011424 SCV004697750 pathogenic Intellectual disability, X-linked syndromic, Turner type criteria provided, single submitter clinical testing
OMIM RCV000011424 SCV000031656 pathogenic Intellectual disability, X-linked syndromic, Turner type 2008-02-01 no assertion criteria provided literature only

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