ClinVar Miner

Submissions for variant NM_022168.4(IFIH1):c.2465G>A (p.Arg822Gln) (rs376048533)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000436896 SCV000517315 pathogenic not provided 2017-12-20 criteria provided, single submitter clinical testing The R822Q variant in the IFIH1 gene has been reported previously in multiple unrelated individuals with Singleton-Merten syndrome (Rutsch et al., 2015; Pettersson et al., 2017). The R822Q has also been reported in an individual with Aicardi-Goutieres syndrome, suggesting that the R822Q variant may be associated with a phenotypic spectrum of IFIH1-related disorders (Buers et al. 2017). The R822Q variant is observed in 6/244,096 (0.0025%) alleles in large population cohorts and no individuals were reported to be homozygous (Lek et al., 2016). The R822Q variant is a semi-conservative amino acid substitution and is located within the second core helicase domain (HEL2) (Rutsch et al., 2015). Functional studies of the R822Q variant demonstrate gain-of-function with increased interferon beta expression (Rutsch et al., 2015). We interpret R822Q as a pathogenic variant.
Blueprint Genetics RCV000436896 SCV000927411 pathogenic not provided 2017-09-20 criteria provided, single submitter clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens RCV000789041 SCV000928386 pathogenic Aicardi-Goutieres syndrome 7 2018-10-02 criteria provided, single submitter clinical testing PS1, PS3, PP1, PP3, PP5
Invitae RCV000822311 SCV000963109 pathogenic Singleton-Merten syndrome 1; Aicardi-Goutieres syndrome 7 2018-10-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 822 of the IFIH1 protein (p.Arg822Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs376048533, ExAC 0.005%). This variant has been observed in individuals and families affected with Singleton–Merten syndrome (PMID: 25620204, 28319323). ClinVar contains an entry for this variant (Variation ID: 189338). Experimental studies have shown that this missense change enhances interferon-beta induction (PMID: 25620204). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000169754 SCV000221304 pathogenic Singleton-Merten syndrome 1 2015-02-05 no assertion criteria provided literature only

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