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

gnomAD frequency: 0.00003  dbSNP: rs376048533

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000436896	SCV000517315	pathogenic	not provided	2022-09-13	criteria provided, single submitter	clinical testing	Published functional studies demonstrate the R822Q variant is gain-of-function with increased interferon beta expression (Rutsch et al., 2015); 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: 25620204, 26284909, 28475458, 28319323, 31898846, 34426522, 31589614)
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	2023-12-30	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 822 of the IFIH1 protein (p.Arg822Gln). This variant is present in population databases (rs376048533, gnomAD 0.005%). This missense change has been observed in individuals with Singleton–Merten syndrome (PMID: 25620204, 28319323). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 189338). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt IFIH1 function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects IFIH1 function (PMID: 25620204). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000436896	SCV001500236	pathogenic	not provided	2023-07-01	criteria provided, single submitter	clinical testing	IFIH1: PP4:Strong, PS1, PP1, PS3:Supporting
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000436896	SCV001905612	pathogenic	not provided	2021-09-15	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000436896	SCV002023125	pathogenic	not provided	2021-11-04	criteria provided, single submitter	clinical testing
3billion	RCV000169754	SCV004013774	pathogenic	Singleton-Merten syndrome 1		criteria provided, single submitter	clinical testing	The variant is observed at an allele frequency greater than expected for the associated disorder in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 25620204). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.98; 3Cnet: 0.92). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000189338 / PMID: 25620204). The variant has been previously reported as de novo in a similarly affected individual (PMID: 25620204). The variant has been observed in at least two similarly affected unrelated individuals (PMID: 25620204). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000436896	SCV004026003	likely pathogenic	not provided	2022-11-18	criteria provided, single submitter	clinical testing	PP3, PP2, PM2_SUP, PS3
Molecular Medicine, University of Pavia	RCV000169754	SCV004026603	likely pathogenic	Singleton-Merten syndrome 1	2023-07-28	criteria provided, single submitter	research
OMIM	RCV000169754	SCV000221304	pathogenic	Singleton-Merten syndrome 1	2015-02-05	no assertion criteria provided	literature only
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000436896	SCV001798454	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000436896	SCV001809561	pathogenic	not provided		no assertion criteria provided	clinical testing
OMIM	RCV000789041	SCV003928202	pathogenic	Aicardi-Goutieres syndrome 7	2015-02-05	no assertion criteria provided	literature only