2-162273913-C-T

Variant names:

• chr2-162273913-C-T
• rs587777446
• NM_022168.4:c.2336G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_022168.4(IFIH1):​c.2336G>A​(p.Arg779His) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,455,194 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R779L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: IFIH1 NM_022168.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 6.15
• Publications: 34 publications found

Genes affected

IFIH1 (HGNC:18873): (interferon induced with helicase C domain 1) IFIH1 encodes MDA5 which is an intracellular sensor of viral RNA that triggers the innate immune response. Sensing RNA length and secondary structure, MDA5 binds dsRNA oligonucleotides with a modified DExD/H-box helicase core and a C-terminal domain, thus leading to a proinflammatory response that includes interferons. It has been shown that Coronaviruses (CoVs) as well as various other virus families, are capable of evading the MDA5-dependent interferon response, thus impeding the activation of the innate immune response to infection. MDA5 has also been shown to play an important role in enhancing natural killer cell function in malaria infection. In addition to its protective role in antiviral responses, MDA5 has been implicated in autoimmune and autoinflammatory diseases such as type 1 diabetes, systemic lupus erythematosus, and Aicardi-Goutieres syndrome[provided by RefSeq, Jul 2020]

IFIH1 Gene-Disease associations (from GenCC):

• Aicardi-Goutieres syndrome 7

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Illumina, Labcorp Genetics (formerly Invitae), G2P
• Singleton-Merten syndrome 1

  Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Aicardi-Goutieres syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Singleton-Merten dysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• immunodeficiency 95

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 11 uncertain in NM_022168.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-162273913-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 812532.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.951
• PP5: Variant 2-162273913-C-T is Pathogenic according to our data. Variant chr2-162273913-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 137622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFIH1	NM_022168.4	c.2336G>A	p.Arg779His	missense_variant	Exon 12 of 16	ENST00000649979.2	NP_071451.2
IFIH1	XM_047445407.1	c.1619G>A	p.Arg540His	missense_variant	Exon 11 of 15		XP_047301363.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFIH1	ENST00000649979.2	c.2336G>A	p.Arg779His	missense_variant	Exon 12 of 16		NM_022168.4	ENSP00000497271.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249336 AF XY: 0.00000742

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1455194 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 724204

African (AFR) AF: 0.00 AC: 0 AN: 33242

American (AMR) AF: 0.00 AC: 0 AN: 44332

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26026

East Asian (EAS) AF: 0.00 AC: 0 AN: 39600

South Asian (SAS) AF: 0.00 AC: 0 AN: 85690

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1107014

Other (OTH) AF: 0.00 AC: 0 AN: 60162

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Aicardi-Goutieres syndrome 7 Pathogenic:4

Aug 01, 2017

Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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.

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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.

Oct 02, 2021

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Same nucleotide change resulting in same amino acid change has been previously reported multiole times as de novoo in similarly affected unrelated individuals (PMID:31898846, PS2, PS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000004, PM2). A different missense change at the same codon (p.Arg779Cys, p.Arg779Leu) has been reported as pathogenic (ClinVar ID: VCV000812532.2, PMID: 31898846, PM5). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.843, 3Cnet: 0.995, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Jul 03, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

not provided Pathogenic:4

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 06, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect (gain of function that increases interferon signaling) (PMID: 24686847); Not observed at significant frequency in large population cohorts (gnomAD); 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: 29158550, 28553952, 24995871, 34189822, 31130681, 25777993, 27658362, 28475458, 29132962, 31623504, 31898846, 32042913, 32508843, 33307271, 33683010, 37273706, 36964972, 36403551, 33057194, 37126154, 37267771, 35982159, 27943079, 35551623, 38693247, 39347527, 38976295, 38077314, 26833990, 24686847)

Immunodeficiency 95 Pathogenic:2

Mar 25, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 25, 2024

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The IFIH1 c.2336G>A p.(Arg779His) missense variant has been identified in a de novo state in several individuals with IFIH1-related interferonopathy (PMID: 31898846). Two additional variants impacting the same amino acid codon and both classified as pathogenic, p.(Arg779Cys) and p.(Arg779Leu), have been reported in individuals with a phenotype consistent with IFIH1-related interferonopathy (PMID: 31898846) . This variant is located in the helicase domain near the ATP binding site (PMID: 31898846). This variant is not observed at a significant frequency in version 2.1.1 or version 4.0.0 of the Genome Aggregation Database. A functional study conducted in human cell lines demonstrated that this variant caused upregulation of type I interferon signaling compared to wild type (PMID: 24686847). This variant has been classified as likely pathogenic or pathogenic by at least three submitters in ClinVar and was identified in a denovo state in the proband. Based on the available evidence, the c.2336G>A p.(Arg779His) variant is classified as pathogenic for IFIH1-related interferonopathy.

Aicardi-Goutieres syndrome 7;C4225427:Singleton-Merten syndrome 1 Pathogenic:2

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 779 of the IFIH1 protein (p.Arg779His). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with Aicardi Goutieres syndrome (PMID: 31898846). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 137622). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt IFIH1 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg779 amino acid residue in IFIH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24686847, 26833990, 31898846). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Clonus;C0151889:Hyperreflexia;C0948163:Abnormal cerebral white matter morphology;C1836830:Developmental regression;C2267233:Neonatal hypotonia;C4025723:Abnormal upper motor neuron morphology;C4520981:Abnormal basal ganglia morphology Pathogenic:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Singleton-Merten syndrome 1 Pathogenic:1

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

IFIH1-related disorder Pathogenic:1

Sep 01, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The IFIH1 c.2336G>A variant is predicted to result in the amino acid substitution p.Arg779His. This variant has been reported to occur de novo in at least three individuals with autosomal dominant Aicardi-Goutieres syndrome 7 (Rice et al. 2014. PubMed ID: 24686847; Oda et al. 2014. PubMed ID: 24995871; Van Eyck et al. 2015. PubMed ID: 25777993). In another family, the variant in the affected proband was inherited from a clinically asymptomatic father and grandmother (Family 259, Rice et al. 2014. PubMed ID: 24686847), indicating variable penetrance. Functional in vitro studies suggest that the p.Arg779His variant results in increased binding to RNA in comparison to the wild-type IFIH1 protein (Rice et al. 2014. PubMed ID: 24686847). In addition, a different amino acid change at this same position has also been reported in Aicardi-Goutieres patients (p.Arg779Cys; Rice GI. et al. 2014. PMID: 24686847). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-163130423-C-T). This variant is interpreted as pathogenic.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.68	D;D;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.78
LIST_S2	Benign	0.0	.;D;D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Uncertain	2.8	M;M;.
PhyloP100		6.2
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	0.0	.;D;.
Sift	Pathogenic	0.0	.;T;.
Sift4G	Pathogenic	0.0	.;T;.
Vest4		0.0
ClinPred		0.93	D
GERP RS		5.6
Varity_R		0.36
gMVP		0.61
Mutation Taster		=10/90	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587777446; hg19: chr2-163130423; COSMIC: COSV55127542;