VCV000137622.42 - ClinVar

NM_022168.4(IFIH1):c.2336G>A (p.Arg779His)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(14)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_022168.4(IFIH1):c.2336G>A (p.Arg779His)

Variation ID: 137622 Accession: VCV000137622.42

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q24.2 2: 162273913 (GRCh38) [ NCBI UCSC ] 2: 163130423 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 11, 2015	Oct 20, 2024	Mar 25, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_022168.4:c.2336G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_071451.2:p.Arg779His	missense
NC_000002.12:g.162273913C>T
NC_000002.11:g.163130423C>T
NG_011495.1:g.49617G>A
LRG_1235:g.49617G>A
LRG_1235t1:c.2336G>A	LRG_1235p1:p.Arg779His
	Q9BYX4:p.Arg779His

... more HGVS ... less HGVS

Protein change

R779H

Other names

Canonical SPDI

NC_000002.12:162273912:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00000

Links

UniProtKB: Q9BYX4#VAR_071382 OMIM: 606951.0002 ClinGen: CA163190 dbSNP: rs587777446 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
IFIH1		-	-	GRCh38 GRCh37	1414	1441

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Aicardi-Goutieres syndrome 7	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Oct 2, 2021	RCV000125471.10
not provided	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Nov 3, 2021	RCV000412770.28
Abnormal basal ganglia morphology Abnormal cerebral white matter morphology Abnormal upper motor neuron morphology Clonus Developmental regression Hyperreflexia Neonatal hypotonia	Likely pathogenic (1)	criteria provided, single submitter	Jan 1, 2017	RCV000626957.3
Aicardi-Goutieres syndrome 7 Singleton-Merten syndrome 1	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Oct 3, 2023	RCV000763454.7
Singleton-Merten syndrome 1	Pathogenic (1)	criteria provided, single submitter	May 4, 2022	RCV001770100.3
Immunodeficiency 95	Pathogenic (1)	criteria provided, single submitter	Mar 25, 2024	RCV003989322.2
IFIH1-related disorder	Pathogenic (1)	no assertion criteria provided	Sep 1, 2024	RCV004745206.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Aug 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Aicardi-Goutieres syndrome 7 (Autosomal dominant inheritance) Affected status: yes Allele origin: maternal	Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg Accession: SCV000586716.1 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015	Comment: 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. … (more) 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. (less) Clinical Features: Intellectual disability (present) Sex: male
Pathogenic (Nov 03, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV002011384.3 First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023
Pathogenic (Oct 03, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Aicardi-Goutieres syndrome 7 Singleton-Merten syndrome 1 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002238373.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 28, 2024	Publications: PubMed (3) PubMed: 31898846‚ 24686847‚ 26833990 Comment: 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). … (more) 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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt IFIH1 protein function. 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. (less)
Pathogenic (Mar 25, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Immunodeficiency 95 Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004806092.1 First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024
Likely pathogenic (Jan 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Abnormal basal ganglia morphology Abnormal cerebral white matter morphology Clonus Developmental regression Hyperreflexia Neonatal hypotonia Abnormal upper motor neuron morphology Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV000747660.1 First in ClinVar: May 12, 2018 Last updated: May 12, 2018
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Aicardi-Goutieres syndrome 7 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Study: Broad Institute Center for Mendelian Genomics (CMG) Accession: SCV000786712.1 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015	Comment: 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 … (more) 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. (less) Number of individuals with the variant: 1 Ethnicity/Population group: Unspecified
Pathogenic (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Singleton-Merten syndrome 1 Aicardi-Goutieres syndrome 7 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000894230.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001447353.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Dystonic disorder (present) , Movement disorder (present) , Hypotonia (present) , Microcephaly (present) , Respiratory insufficiency (present) , Hepatomegaly (present) Sex: male
Pathogenic (May 14, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000491225.2 First in ClinVar: Jan 09, 2017 Last updated: Apr 17, 2019	Comment: Published functional studies demonstrate a damaging effect (gain of function that increases interferon signaling) (Rice et al., 2014); Not observed at a significant frequency in … (more) Published functional studies demonstrate a damaging effect (gain of function that increases interferon signaling) (Rice et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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, 31130681, 24686847, 25777993, 27658362, 28475458, 29132962, 31623504, 31898846, 32042913, 32508843) (less)
Pathogenic (Oct 02, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Aicardi-Goutieres syndrome 7 Affected status: yes Allele origin: germline	3billion Accession: SCV002012154.1 First in ClinVar: Nov 11, 2021 Last updated: Nov 11, 2021	Publications: PubMed (1) PubMed: 31898846 Comment: 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, … (more) 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. (less) Clinical Features: Delayed speech and language development (present) , Delayed fine motor development (present) , Delayed gross motor development (present) , Intellectual disability (present) , Spasticity (present) … (more) Delayed speech and language development (present) , Delayed fine motor development (present) , Delayed gross motor development (present) , Intellectual disability (present) , Spasticity (present) , Cerebral palsy (present) , Global developmental delay (present) (less)
Pathogenic (May 04, 2022)	criteria provided, single submitter (Mendelics Assertion Criteria 2019) Method: clinical testing	Singleton-Merten syndrome 1 Affected status: unknown Allele origin: germline	Mendelics Accession: SCV002516569.1 First in ClinVar: May 28, 2022 Last updated: May 28, 2022
Pathogenic (Jan 01, 2020)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001248324.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 2
Pathogenic (Jul 03, 2014)	no assertion criteria provided Method: literature only	AICARDI-GOUTIERES SYNDROME 7 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000168923.5 First in ClinVar: Jun 23, 2014 Last updated: Mar 12, 2022	Publications: PubMed (2) PubMed: 24686847‚ 24995871 Comment on evidence: In 2 unrelated patients with Aicardi-Goutieres syndrome-7 (AGS7; 615846), Rice et al. (2014) identified a heterozygous c.2336G-A transition in exon 12 of the IFIH1 gene, … (more) In 2 unrelated patients with Aicardi-Goutieres syndrome-7 (AGS7; 615846), Rice et al. (2014) identified a heterozygous c.2336G-A transition in exon 12 of the IFIH1 gene, resulting in an arg779-to-his (R779H) substitution at a highly conserved residue in the core helicase-2 domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the Exome Sequencing Project database or in over 300 in-house control exomes. The mutation occurred de novo in 1 patient. In the second family, the clinically asymptomatic father and paternal grandmother also carried the mutation, suggesting incomplete penetrance. However, all 3 mutation carriers in this family had a robust interferon signature. Rice et al. (2014) suggested that the phenotypic variability in this family may have resulted from additional environmental or genetic factors. In vitro functional expression assays in HEK293T cells showed that the mutation caused marked induction of interferon signaling in response to short 162-bp double-stranded RNA (dsRNA) compared to controls. The mutation conferred 4- to 10-fold higher levels of basal signaling activity even in the absence of exogenous ligand. These findings were consistent with a gain of function, resulting in increased interferon signaling. Oda et al. (2014) identified a de novo heterozygous R779H mutation in a Japanese girl with AGS7. The mutation was found by trio-based whole-exome sequencing and confirmed by Sanger sequencing. (less)
Pathogenic (Sep 01, 2024)	no assertion criteria provided Method: clinical testing	IFIH1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005362177.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: 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 … (more) 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. (less)
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Comment:

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.

Comment:

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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt IFIH1 protein function. 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.

Comment:

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.

Comment:

Published functional studies demonstrate a damaging effect (gain of function that increases interferon signaling) (Rice et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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, 31130681, 24686847, 25777993, 27658362, 28475458, 29132962, 31623504, 31898846, 32042913, 32508843)

Comment:

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.

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Genetic and phenotypic spectrum associated with IFIH1 gain-of-function.	Rice GI	Human mutation	2020	PMID: 31898846
Clinical and pathologic features of Aicardi-Goutières syndrome due to an IFIH1 mutation: A pediatric case report.	Marguet F	American journal of medical genetics. Part A	2016	PMID: 26833990
Aicardi-Goutières syndrome is caused by IFIH1 mutations.	Oda H	American journal of human genetics	2014	PMID: 24995871
Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling.	Rice GI	Nature genetics	2014	PMID: 24686847

Text-mined citations for rs587777446 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_022168.4(IFIH1):c.2336G>A (p.Arg779His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs587777446 ...