ClinVar Miner

Submissions for variant NM_031407.7(HUWE1):c.329G>A (p.Arg110Gln)

dbSNP: rs1557036768
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital RCV000497788 SCV000503003 pathogenic Intellectual disability, X-linked syndromic, Turner type 2017-01-18 criteria provided, single submitter clinical testing
Undiagnosed Diseases Network, NIH RCV000497788 SCV000863412 pathogenic Intellectual disability, X-linked syndromic, Turner type 2018-09-04 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000497788 SCV001190300 pathogenic Intellectual disability, X-linked syndromic, Turner type 2019-08-20 criteria provided, single submitter clinical testing
GeneDx RCV001571522 SCV001796016 pathogenic not provided 2020-12-21 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); 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: 32336296, 29180823, 29307790, 25985138)
Mendelics RCV000497788 SCV002516566 pathogenic Intellectual disability, X-linked syndromic, Turner type 2022-05-04 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000497788 SCV002766475 pathogenic Intellectual disability, X-linked syndromic, Turner type 2022-11-22 criteria provided, single submitter clinical testing Variant summary: HUWE1 c.329G>A (p.Arg110Gln) results in a conservative amino acid change located in a domain of unknown function DUF908 (IPR010309) in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183017 control chromosomes (gnomAD). c.329G>A has been reported in the literature as a de novo variant in the heterozygous state in three female individuals affected with intellectual disability and craniosynostosis (e.g. Taylor_2015, Moortgat_2018). In all three cases, these individuals exhibited skewed X-inactivation of the wildtype X chromosome, resulting in preferential expression of the variant allele. These data indicate that the variant is likely associated with disease. Furthermore, a different missense change at the same amino acid, p.Arg110Trp, has been observed in at least one hemizygous male with similar clinical features (e.g. Taylor_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV001571522 SCV003445157 pathogenic not provided 2023-08-17 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 110 of the HUWE1 protein (p.Arg110Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with HUWE1-related conditions (PMID: 25985138, 29180823). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 375709). 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. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV002524683 SCV003752368 pathogenic Inborn genetic diseases 2020-10-09 criteria provided, single submitter clinical testing The c.329G>A (p.R110Q) alteration is located in exon 6 (coding exon 3) of the HUWE1 gene. This alteration results from a G to A substitution at nucleotide position 329, causing the arginine (R) at amino acid position 110 to be replaced by a glutamine (Q). Based on data from the Genome Aggregation Database (gnomAD), the HUWE1 c.329G>A alteration was not observed, with coverage at this position. This alteration was described as a recurrent de novo alteration in female patients with a neurodevelopmental syndrome that included motor delays, mild intellectual disability, skeletal anomalies, craniosynostosis, and facial dysmorphic features. All females showed skewed inactivation of the X chromosome favoring the affected allele (Taylor, 2015; Moortgat, 2018). The p.R110 amino acid is conserved in available vertebrate species. The p.R110Q alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare RCV000497788 SCV000863839 pathogenic Intellectual disability, X-linked syndromic, Turner type 2018-03-23 no assertion criteria provided clinical testing
OMIM RCV000497788 SCV000902279 pathogenic Intellectual disability, X-linked syndromic, Turner type 2021-08-20 no assertion criteria provided literature only

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