ClinVar Miner

Submissions for variant NM_022168.4(IFIH1):c.2336G>A (p.Arg779His) (rs587777446)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Broad Institute Rare Disease Group,Broad Institute RCV000125471 SCV000786712 pathogenic Aicardi-Goutieres syndrome 7 criteria provided, single submitter research The heterozygous p.Arg779His variant was identified by our study in one individual with Aicardi-Goutieres syndrome. Trio analysis showed this variant to be de novo. The p.Arg779His variant is believed to be pathogenic based on numberous reports by other laboratories in the literature and databases.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626957 SCV000747660 likely pathogenic Hyperreflexia; Clonus; Neonatal hypotonia; Abnormal upper motor neuron morphology; Abnormality of the basal ganglia; Developmental regression; Abnormality of the cerebral white matter 2017-01-01 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763454 SCV000894230 pathogenic Singleton-Merten syndrome 1; Aicardi-Goutieres syndrome 7 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000412770 SCV000491225 pathogenic not provided 2018-11-30 criteria provided, single submitter clinical testing The R779H variant in the IFIH1 gene has been reported previously in association with Aicardi-Goutieres syndrome (AGS) in multiple unrelated affected individuals (Rice et al., 2014; Oda et al., 2014; Buers et al., 2017). The R779H variant was also identified in one individual with severe early-onset and refractory systemic lupus erythematosus, IgA deficiency, and mild lower limb spasticity (Van Eyck et al., 2015). The father and paternal grandmother of one patient with AGS, were found to also be heterozygous for R779H, and had a robust interferon signature consistent with the affected child's, but the father and grandmother were clinically unaffected (Rice et al., 2014). The R779H variant is not observed in large population cohorts (Lek et al., 2016). The R779H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Cellular and biochemical assays indicate that this variant increased interferon activity and binds RNA more avidly and tightly than wild-type protein, which confers gain of function (Rice et al., 2014). A different variant at this same codon (R779C) has been reported in association with Aicardi-Goutieres syndrome (Rice et al., 2014; Marguet et al., 2016), supporting the functional importance of this region of the protein. We interpret R779H as a pathogenic variant.
Institute of Human Genetics,Friedrich-Alexander-Universität Erlangen-Nürnberg RCV000125471 SCV000586716 pathogenic Aicardi-Goutieres syndrome 7 2017-08-01 criteria provided, single submitter clinical testing Missense variant previously described as pathogenic was identified in a patient with initially normal development, regression, severe ID, spasticity, scoliosis, episodic icterus and skin swelling. The variant was inherited from the healthy mother.
OMIM RCV000125471 SCV000168923 pathogenic Aicardi-Goutieres syndrome 7 2014-07-03 no assertion criteria provided literature only

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