ClinVar Genomic variation as it relates to human health
NM_022489.4(INF2):c.653G>A (p.Arg218Gln)
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_022489.4(INF2):c.653G>A (p.Arg218Gln)
Variation ID: 1051 Accession: VCV000001051.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q32.33 14: 104703440 (GRCh38) [ NCBI UCSC ] 14: 105169777 (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 4, 2013 May 1, 2024 Oct 29, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_022489.4:c.653G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_071934.3:p.Arg218Gln missense NM_001031714.4:c.653G>A NP_001026884.3:p.Arg218Gln missense NM_032714.3:c.653G>A NP_116103.1:p.Arg218Gln missense NC_000014.9:g.104703440G>A NC_000014.8:g.105169777G>A NG_027684.1:g.18835G>A Q27J81:p.Arg218Gln - Protein change
- R218Q
- Other names
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- Canonical SPDI
- NC_000014.9:104703439:G:A
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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
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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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INF2 | - | - |
GRCh38 GRCh37 |
1461 | 1546 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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 (5) |
criteria provided, single submitter
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Sep 1, 2022 | RCV000001106.8 | |
Pathogenic (2) |
criteria provided, single submitter
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Jun 2, 2023 | RCV000681691.2 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 29, 2023 | RCV001239762.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 7, 2022 | RCV002293970.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Aug 10, 2023 | RCV003352745.2 |
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
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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
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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 07, 2022)
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criteria provided, single submitter
Method: clinical testing
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Kidney disorder
Affected status: unknown
Allele origin:
germline
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Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002587339.1
First in ClinVar: Oct 29, 2022 Last updated: Oct 29, 2022 |
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Likely pathogenic
(Aug 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV004076092.2
First in ClinVar: Oct 28, 2023 Last updated: May 01, 2024 |
Comment:
The c.653G>A (p.R218Q) alteration is located in exon 4 (coding exon 3) of the INF2 gene. This alteration results from a G to A substitution … (more)
The c.653G>A (p.R218Q) alteration is located in exon 4 (coding exon 3) of the INF2 gene. This alteration results from a G to A substitution at nucleotide position 653, causing the arginine (R) at amino acid position 218 to be replaced by a glutamine (Q). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration was detected in the heterozygous state in multiple individuals with focal segmental glomerulosclerosis and cosegregates with disease in several families (Morales-Alvarez, 2022; Schrezenmeier, 2021; Seo, 2020; Connaughton, 2019; Bezdíka, 2018; Safarikova, 2018; Caridi, 2014; Brown, 2010). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). Functional studies collectively show a critical impact of R218Q on the function of INF2 in various model systems and multiple different assays (Sun, 2021; A, 2019). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. (less)
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Pathogenic
(Sep 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Focal segmental glomerulosclerosis 5
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002573111.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Functional studies provide supporting evidence of the variant … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product (PMID: 20023659). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.76; 3Cnet: 0.15). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000001051). The variant has been observed in at least two similarly affected unrelated individuals (PMID: 20023659 , 30773290). A different missense change at the same codon (p.Arg218Trp) has been reported to be associated with INF2-related disorder (ClinVar ID: VCV000001052 / PMID: 20023659 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Proteinuria (present)
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Pathogenic
(Apr 08, 2022)
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criteria provided, single submitter
Method: clinical testing
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Focal segmental glomerulosclerosis 5
Charcot-Marie-Tooth disease dominant intermediate E
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV001752547.2
First in ClinVar: Jul 18, 2021 Last updated: Dec 31, 2022 |
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Pathogenic
(Jun 02, 2023)
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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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004226883.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP1_strong, PP3, PM1, PM2_supporting, PS3, PS4_moderate
Number of individuals with the variant: 1
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Pathogenic
(Oct 29, 2023)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease dominant intermediate E
Focal segmental glomerulosclerosis 5
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: SCV001412659.5
First in ClinVar: Jul 16, 2020 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 218 of the INF2 protein (p.Arg218Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 218 of the INF2 protein (p.Arg218Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with focal segmental glomerulosclerosis (FSGS) (PMID: 20023659, 25165188; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1051). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on INF2 protein function. Experimental studies have shown that this missense change affects INF2 function (PMID: 20023659, 26764407). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 01, 2010)
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no assertion criteria provided
Method: literature only
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FOCAL SEGMENTAL GLOMERULOSCLEROSIS 5
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000021256.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In affected members of a large family segregating autosomal dominant focal segmental glomerulosclerosis (FSGS5; 613237), Brown et al. (2010) identified a heterozygous alteration in exon … (more)
In affected members of a large family segregating autosomal dominant focal segmental glomerulosclerosis (FSGS5; 613237), Brown et al. (2010) identified a heterozygous alteration in exon 4 of the INF2 gene, resulting in an arg218-to-gln (R218Q) substitution at a conserved residue within the DID. Structural modeling revealed that the R218 residue lies close to the DAD-binding region of the DID, and transfection studies in cultured podocytes showed a finer, more diffuse distribution of INF2 and less prominent stress fibers and cortical actin with mutant compared to wildtype INF2. The mutation was not found in 682 control chromosomes. Age at diagnosis in this kindred ranged from 22 years to 45 years; 4 of 10 affected individuals developed end-stage renal disease, with age of onset ranging from 23 years to 30 years. (less)
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Pathogenic
(Sep 16, 2018)
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no assertion criteria provided
Method: research
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not provided
Affected status: yes
Allele origin:
germline
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Gharavi Laboratory, Columbia University
Accession: SCV000809139.1
First in ClinVar: Oct 01, 2018 Last updated: Oct 01, 2018 |
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Pathogenic
(Feb 14, 2019)
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no assertion criteria provided
Method: literature only
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Focal segmental glomerulosclerosis 5
Affected status: yes
Allele origin:
germline
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Yale Center for Mendelian Genomics, Yale University
Study: Yale Center for Mendelian Genomics
Accession: SCV002106620.1 First in ClinVar: Mar 28, 2022 Last updated: Mar 28, 2022 |
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Pathogenic
(May 17, 2018)
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no assertion criteria provided
Method: clinical testing
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Focal segmental glomerulosclerosis 5
Affected status: yes
Allele origin:
germline
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Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare
Accession: SCV000863868.1
First in ClinVar: Dec 24, 2018 Last updated: Dec 24, 2018 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Focal segmental glomerulosclerosis 5
Affected status: yes
Allele origin:
germline
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Genomics England Pilot Project, Genomics England
Accession: SCV001760330.1
First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 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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Clinical and Pathological Heterogeneity in FSGS due to INF2 Mutations. | Morales-Alvarez MC | Kidney international reports | 2022 | PMID: 36506246 |
The underestimated burden of monogenic kidney disease in adults waitlisted for kidney transplantation. | Schrezenmeier E | Genetics in medicine : official journal of the American College of Medical Genetics | 2021 | PMID: 33712733 |
Dysregulated Dynein-Mediated Trafficking of Nephrin Causes INF2-related Podocytopathy. | Sun H | Journal of the American Society of Nephrology : JASN | 2021 | PMID: 33443052 |
Diagnostic yield and clinical utility of whole exome sequencing using an automated variant prioritization system, EVIDENCE. | Seo GH | Clinical genetics | 2020 | PMID: 32901917 |
FSGS-Causing INF2 Mutation Impairs Cleaved INF2 N-Fragment Functions in Podocytes. | Subramanian B | Journal of the American Society of Nephrology : JASN | 2020 | PMID: 31924668 |
A complex containing lysine-acetylated actin inhibits the formin INF2. | A M | Nature cell biology | 2019 | PMID: 30962575 |
Monogenic causes of chronic kidney disease in adults. | Connaughton DM | Kidney international | 2019 | PMID: 30773290 |
Diagnostic Utility of Exome Sequencing for Kidney Disease. | Groopman EE | The New England journal of medicine | 2019 | PMID: 30586318 |
Mutational screening of inverted formin 2 in adult-onset focal segmental glomerulosclerosis or minimal change patients from the Czech Republic. | Safarikova M | BMC medical genetics | 2018 | PMID: 30126379 |
Genetic diagnosis of steroid-resistant nephrotic syndrome in a longitudinal collection of Czech and Slovak patients: a high proportion of causative variants in NUP93. | Bezdíčka M | Pediatric nephrology (Berlin, Germany) | 2018 | PMID: 29869118 |
Disease causing mutations in inverted formin 2 regulate its binding to G-actin, F-actin capping protein (CapZ α-1) and profilin 2. | Rollason R | Bioscience reports | 2016 | PMID: 26764407 |
Human Kidney Disease-causing INF2 Mutations Perturb Rho/Dia Signaling in the Glomerulus. | Sun H | EBioMedicine | 2014 | PMID: 26086034 |
Novel INF2 mutations in an Italian cohort of patients with focal segmental glomerulosclerosis, renal failure and Charcot-Marie-Tooth neuropathy. | Caridi G | Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association | 2014 | PMID: 25165188 |
Genetic screening in adolescents with steroid-resistant nephrotic syndrome. | Lipska BS | Kidney international | 2013 | PMID: 23515051 |
Mutations in the formin gene INF2 cause focal segmental glomerulosclerosis. | Brown EJ | Nature genetics | 2010 | PMID: 20023659 |
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Text-mined citations for rs267607183 ...
HelpRecord last updated May 01, 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.