ClinVar Genomic variation as it relates to human health
NM_022168.4(IFIH1):c.2465G>A (p.Arg822Gln)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_022168.4(IFIH1):c.2465G>A (p.Arg822Gln)
Variation ID: 189338 Accession: VCV000189338.48
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q24.2 2: 162272377 (GRCh38) [ NCBI UCSC ] 2: 163128887 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Apr 11, 2015 May 12, 2024 Dec 30, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_022168.4:c.2465G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_071451.2:p.Arg822Gln missense NC_000002.12:g.162272377C>T NC_000002.11:g.163128887C>T NG_011495.1:g.51153G>A LRG_1235:g.51153G>A LRG_1235t1:c.2465G>A LRG_1235p1:p.Arg822Gln Q9BYX4:p.Arg822Gln - Protein change
- R822Q
- Other names
- IFIH1, ARG822GLN (rs376048533)
- Canonical SPDI
- NC_000002.12:162272376:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00002
Exome Aggregation Consortium (ExAC) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00003
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
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 | ||
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HI score
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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. |
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IFIH1 | - | - |
GRCh38 GRCh37 |
1398 | 1425 |
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. |
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Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jul 28, 2023 | RCV000169754.16 | |
Pathogenic/Likely pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Jul 1, 2023 | RCV000436896.35 | |
Pathogenic (2) |
criteria provided, single submitter
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Oct 2, 2018 | RCV000789041.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 30, 2023 | RCV000822311.12 |
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. |
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Pathogenic
(Sep 15, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001905612.1
First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 2021 |
Clinical Features:
Abnormality of the tongue (present) , Intellectual disability (present) , Abnormal corpus callosum morphology (present) , Spastic tetraparesis (present) , Gait disturbance (present) , Congenital … (more)
Abnormality of the tongue (present) , Intellectual disability (present) , Abnormal corpus callosum morphology (present) , Spastic tetraparesis (present) , Gait disturbance (present) , Congenital omphalocele (present) , Clubfoot (present) , Hypoglycemia (present) , Gait ataxia (present) , Ventriculomegaly (present) , Tetraparesis (present) , Intestinal obstruction (present) , Periventricular leukomalacia (present) , Axial hypotonia (present) (less)
Sex: male
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Pathogenic
(Sep 13, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000517315.5
First in ClinVar: Mar 08, 2017 Last updated: Mar 04, 2023 |
Comment:
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 … (more)
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) (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Singleton-Merten syndrome 1
Affected status: yes
Allele origin:
unknown
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3billion
Accession: SCV004013774.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Glaucoma of childhood (present) , Abnormality of the dentition (present) , Scoliosis (present) , Abnormal foot morphology (present) , Eczematoid dermatitis (present) , Hypopigmentation of … (more)
Glaucoma of childhood (present) , Abnormality of the dentition (present) , Scoliosis (present) , Abnormal foot morphology (present) , Eczematoid dermatitis (present) , Hypopigmentation of the skin (present) , Hyperpigmentation of the skin (present) (less)
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Likely pathogenic
(Nov 18, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV004026003.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
Comment:
PP3, PP2, PM2_SUP, PS3
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Pathogenic
(Oct 02, 2018)
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criteria provided, single submitter
Method: clinical testing
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Aicardi-Goutieres syndrome 7
Affected status: yes
Allele origin:
germline
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Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV000928386.1
First in ClinVar: Jul 27, 2019 Last updated: Jul 27, 2019 |
Comment:
PS1, PS3, PP1, PP3, PP5
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Pathogenic
(Sep 20, 2017)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV000927411.1
First in ClinVar: Jul 27, 2019 Last updated: Jul 27, 2019
Comment:
Patient analyzed with Primary Immunodeficiency Panel
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Likely pathogenic
(Jul 28, 2023)
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criteria provided, single submitter
Method: research
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Singleton-Merten syndrome 1
Affected status: yes
Allele origin:
paternal
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Molecular Medicine, University of Pavia
Accession: SCV004026603.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
Number of individuals with the variant: 1
Secondary finding: no
Method: Whole-exome sequencing
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Pathogenic
(Nov 04, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002023125.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Dec 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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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
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Invitae
Accession: SCV000963109.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024 |
Comment:
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). … (more)
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. (less)
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Pathogenic
(Jul 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001500236.18
First in ClinVar: Mar 14, 2021 Last updated: May 12, 2024 |
Comment:
IFIH1: PP4:Strong, PS1, PP1, PS3:Supporting
Number of individuals with the variant: 4
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Pathogenic
(Feb 05, 2015)
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no assertion criteria provided
Method: literature only
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SINGLETON-MERTEN SYNDROME 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000221304.3
First in ClinVar: Apr 11, 2015 Last updated: Jun 03, 2023 |
Comment on evidence:
Singleton-Merten Syndrome 1 In affected individuals from 3 unrelated families with early and extreme aortic and valvular calcification, dental anomalies, osteopenia, and acroosteolysis (SGMRT1; 182250), … (more)
Singleton-Merten Syndrome 1 In affected individuals from 3 unrelated families with early and extreme aortic and valvular calcification, dental anomalies, osteopenia, and acroosteolysis (SGMRT1; 182250), previously reported by Feigenbaum et al. (1988), Rutsch et al. (2005), and Valverde et al. (2010), respectively, Rutsch et al. (2015) performed whole-exome sequencing and identified heterozygosity for a c.2465G-A transition in the IFIH1 gene, resulting in an arg822-to-gln (R822Q) substitution at a highly conserved residue in 1 of 2 core helicase domains. The mutation, which segregated with disease in each family, was not found in any unaffected family members; analysis of 17 additional family members from the largest family showed that all but 1 individual with dental anomalies carried the mutation, and 1 individual with only psoriasis carried the mutation, whereas 3 others with only psoriasis did not. The authors noted that the IFIH1 c.2465G-A variant has been reported as a SNP (rs376048533) in 1 individual with 'cardiac and pulmonary phenotypes' from among 6,517 individuals in the NHLBI Exome Variant Server database, and is listed in the Exome Aggregation Consortium Browser with an allele frequency of 0.00002481. In vitro functional analysis revealed that the R822Q mutant enhanced MDA5 function in interferon-beta (IFNB1; 147640) induction, and interferon signature genes were upregulated in patient blood and dental cells. Rutsch et al. (2015) concluded that R822Q is a gain-of-function substitution that causes Singleton-Merten syndrome through dysregulation of the human innate immune response. In a 10-year-old boy with Singleton-Merten syndrome, Riou et al. (2022) identified heterozygosity for the recurrent R822Q mutation (c.2465G-A, NM_022168.4) in the IFIH1 gene. The mutation arose de novo. Aicardi-Goutieres Syndrome 7 In a 6-year-old boy with bilateral spasticity, developmental delay, and basal ganglia calcification (AGS7; 615846), Buers et al. (2017) identified heterozygosity for the R822Q mutation in the IFIH1 gene. The mutation was not present in parental DNA and was considered to have arisen de novo. (less)
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Pathogenic
(Feb 05, 2015)
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no assertion criteria provided
Method: literature only
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AICARDI-GOUTIERES SYNDROME 7
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV003928202.1
First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023 |
Comment on evidence:
Singleton-Merten Syndrome 1 In affected individuals from 3 unrelated families with early and extreme aortic and valvular calcification, dental anomalies, osteopenia, and acroosteolysis (SGMRT1; 182250), … (more)
Singleton-Merten Syndrome 1 In affected individuals from 3 unrelated families with early and extreme aortic and valvular calcification, dental anomalies, osteopenia, and acroosteolysis (SGMRT1; 182250), previously reported by Feigenbaum et al. (1988), Rutsch et al. (2005), and Valverde et al. (2010), respectively, Rutsch et al. (2015) performed whole-exome sequencing and identified heterozygosity for a c.2465G-A transition in the IFIH1 gene, resulting in an arg822-to-gln (R822Q) substitution at a highly conserved residue in 1 of 2 core helicase domains. The mutation, which segregated with disease in each family, was not found in any unaffected family members; analysis of 17 additional family members from the largest family showed that all but 1 individual with dental anomalies carried the mutation, and 1 individual with only psoriasis carried the mutation, whereas 3 others with only psoriasis did not. The authors noted that the IFIH1 c.2465G-A variant has been reported as a SNP (rs376048533) in 1 individual with 'cardiac and pulmonary phenotypes' from among 6,517 individuals in the NHLBI Exome Variant Server database, and is listed in the Exome Aggregation Consortium Browser with an allele frequency of 0.00002481. In vitro functional analysis revealed that the R822Q mutant enhanced MDA5 function in interferon-beta (IFNB1; 147640) induction, and interferon signature genes were upregulated in patient blood and dental cells. Rutsch et al. (2015) concluded that R822Q is a gain-of-function substitution that causes Singleton-Merten syndrome through dysregulation of the human innate immune response. In a 10-year-old boy with Singleton-Merten syndrome, Riou et al. (2022) identified heterozygosity for the recurrent R822Q mutation (c.2465G-A, NM_022168.4) in the IFIH1 gene. The mutation arose de novo. Aicardi-Goutieres Syndrome 7 In a 6-year-old boy with bilateral spasticity, developmental delay, and basal ganglia calcification (AGS7; 615846), Buers et al. (2017) identified heterozygosity for the R822Q mutation in the IFIH1 gene. The mutation was not present in parental DNA and was considered to have arisen de novo. (less)
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001798454.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001809561.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Oral Phenotype of Singleton-Merten Syndrome: A Systematic Review Illustrated With a Case Report. | Riou MC | Frontiers in genetics | 2022 | PMID: 35754802 |
MDA5-Associated Neuroinflammation and the Singleton-Merten Syndrome: Two Faces of the Same Type I Interferonopathy Spectrum. | Buers I | Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research | 2017 | PMID: 28475458 |
Further evidence for specific IFIH1 mutation as a cause of Singleton-Merten syndrome with phenotypic heterogeneity. | Pettersson M | American journal of medical genetics. Part A | 2017 | PMID: 28319323 |
A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome. | Rutsch F | American journal of human genetics | 2015 | PMID: 25620204 |
Singleton-merten syndrome and impaired cardiac function. | Valverde I | Journal of the American College of Cardiology | 2010 | PMID: 21070929 |
Feigenbaum, A., Kumar, A., Weksberg, R. Singleton-Merten (S-M) syndrome: autosomal dominant transmission with variable expression. (Abstract) Am. J. Hum. Genet. 43: A48-only, 1988. | - | - | - | - |
Rutsch, F., Kehl, H. G., Ruf, N., Vogt, J., Kleinheinz, J., Rauch, F., Hofbauer, L. C., Rehder, H., Arslan-Kirchner, M., Nurnberg, P. Singleton-Merten syndrome: evidence of autosomal dominant inheritance in the first European family. (Abstract) Europ. J. Hum. Genet. 13: 112-113 (P0154), 2005. | - | - | - | - |
Text-mined citations for rs376048533 ...
HelpRecord last updated May 12, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.