ClinVar Miner

Submissions for variant NM_031407.7(HUWE1):c.9208C>T (p.Arg3070Cys) (rs886041876)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000406579 SCV000330662 pathogenic not provided 2018-04-03 criteria provided, single submitter clinical testing The R3070C variant in the HUWE1 gene has been reported previously as a de novo variant by whole exome sequencing trio analysis, in two unrelated females with intellectual disability, developmental delays, behavioral differences, and facial dysmorphism, all of variable severity (Moortgat et al., 2018). The R3070C variant is not observed in large population cohorts (Lek et al., 2016). The R3070C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret R3070C as a pathogenic variant.
Center for Medical Genetics and Molecular Medicine,Haukeland University Hospital RCV000497622 SCV000503011 likely pathogenic Mental retardation, X-linked, syndromic, Turner type 2017-01-18 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000497622 SCV000894494 pathogenic Mental retardation, X-linked, syndromic, Turner type 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000406579 SCV000959934 pathogenic not provided 2018-09-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 3070 of the HUWE1 protein (p.Arg3070Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in individuals affected with HUWE1-related disease (PMID:  29180823). ClinVar contains an entry for this variant (Variation ID: 280723). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.

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