Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 22850414, PS3_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000007872, PMID:10425035,9054935,9780098, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.766, 3CNET: 0.902, PP3_P). A missense variant is a common mechanism associated with Corneal dystrophy (PP2_P). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
ClinVar Genomic variation as it relates to human health
NM_000358.3(TGFBI):c.371G>A (p.Arg124His)
Germline
Classification
Help
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.
(7)
Help
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
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000358.3(TGFBI):c.371G>A (p.Arg124His)
Variation ID: 7869 Accession: VCV000007869.13
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 5q31.1 5: 136046407 (GRCh38) [ NCBI UCSC ] 5: 135382096 (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 Apr 4, 2013 Oct 8, 2024 Feb 9, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000358.3:c.371G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000349.1:p.Arg124His missense NC_000005.10:g.136046407G>A NC_000005.9:g.135382096G>A NG_012646.1:g.22513G>A Q15582:p.Arg124His - Protein change
- R124H
- Other names
- -
- Canonical SPDI
- NC_000005.10:136046406:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00004
Exome Aggregation Consortium (ExAC) 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00001
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| TGFBI | - | - |
GRCh38 GRCh37 |
151 | 178 | |
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. |
|---|---|---|---|---|
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Feb 9, 2024 | RCV000008318.9 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 14, 2024 | RCV001543464.5 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 3, 2022 | RCV001807721.1 |
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. |
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|---|---|---|---|---|---|
|
Pathogenic
(Jun 17, 2021)
|
criteria provided, single submitter
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: SCV001762048.1
First in ClinVar: Jul 30, 2021 Last updated: Jul 30, 2021 |
Clinical Features:
Cone-rod dystrophy (present) , Granular corneal dystrophy (present)
Sex: male
|
|
|
Pathogenic
(Jan 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Lattice corneal dystrophy Type I
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002058203.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 22850414, PS3_S). A different missense change … (more)
Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 22850414, PS3_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000007872, PMID:10425035,9054935,9780098, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.766, 3CNET: 0.902, PP3_P). A missense variant is a common mechanism associated with Corneal dystrophy (PP2_P). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Atrial arrhythmia (present) , Cardiac arrhythmia (present) , Corneal opacity (present)
|
|
|
Pathogenic
(May 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Avellino corneal dystrophy
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV005329273.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The observed missense variant c.371G>A(p.Arg124His) in the TGFBI gene has been reported previously in individual(s) with autosomal dominant corneal dystrophy (Nagano C, et al., 2019; … (more)
The observed missense variant c.371G>A(p.Arg124His) in the TGFBI gene has been reported previously in individual(s) with autosomal dominant corneal dystrophy (Nagano C, et al., 2019; Jozaei R, et al.,2022). Experimental studies have shown that this missense change affects TGFBI function (Nielsen NS, et al., 2021). This variant disrupts the p.Arg124 amino acid residue in TGFBI. Other variant(s) that disrupt this residue have been determined to be pathogenic (Grothe HL, et al., 2013; Munier FL, et al., 2002). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant is reported with the allele frequency 0.004% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic. The amino acid Arginine at position 124 is changed to a Histidine changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The residue is conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Abnormality of the eye (present)
|
|
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Pathogenic
(Jan 14, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003439284.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 124 of the TGFBI protein (p.Arg124His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 124 of the TGFBI protein (p.Arg124His). This variant is present in population databases (rs121909211, gnomAD 0.05%). This missense change has been observed in individuals with autosomal dominant corneal dystrophy (PMID: 11923233). ClinVar contains an entry for this variant (Variation ID: 7869). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TGFBI function (PMID: 26197481, 34097874). This variant disrupts the p.Arg124 amino acid residue in TGFBI. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10798644, 11923233, 23559853). 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
(Sep 20, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Avellino corneal dystrophy
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV001981649.3
First in ClinVar: Oct 25, 2021 Last updated: Dec 17, 2022 |
|
|
|
Pathogenic
(Feb 09, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Avellino corneal dystrophy
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV004698058.1
First in ClinVar: Mar 10, 2024 Last updated: Mar 10, 2024 |
Comment:
Criteria applied: PS4,PM5_STR,PS3_MOD,PP3
Clinical Features:
High myopia (present) , Astigmatism (present) , Amblyopia (present) , Corneal dystrophy (present)
Sex: male
|
|
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Pathogenic
(Apr 01, 2004)
|
no assertion criteria provided
Method: literature only
|
CORNEAL DYSTROPHY, AVELLINO TYPE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000028526.2
First in ClinVar: Apr 04, 2013 Last updated: Feb 15, 2020 |
Comment on evidence:
In 2 families with the Avellino type of corneal dystrophy (CDA; 607541), Munier et al. (1997) found that affected members had a mutation of the … (more)
In 2 families with the Avellino type of corneal dystrophy (CDA; 607541), Munier et al. (1997) found that affected members had a mutation of the TGFBI gene in the CpG dinucleotide of an arginine codon, resulting in an arg124-to-his (R124H) amino acid substitution. The diseases resulting from mutations in codon 124 (see also 601692.0003) were accompanied by amyloid deposits, suggesting that the R124-mutated keratoepithelin forms amyloidogenic intermediates that precipitate in the cornea. In the first African American with Avellino corneal dystrophy, Meallet et al. (2004) identified the R124H mutation in heterozygous state. The patient had multiple crumb-like opacities in the anterior corneal stroma of both eyes. Deep to those lesions were numerous faint, stellate lattice lesions. Corneal scraping confirmed the presence of both Masson trichrome and Congo red-positive subepithelial deposits. In addition, there were surface changes resembling vortex dystrophy (verticillata) and large granular deposits protruding through the anterior corneal surface. (less)
|
Comment:
Comment:
The observed missense variant c.371G>A(p.Arg124His) in the TGFBI gene has been reported previously in individual(s) with autosomal dominant corneal dystrophy (Nagano C, et al., 2019; Jozaei R, et al.,2022). Experimental studies have shown that this missense change affects TGFBI function (Nielsen NS, et al., 2021). This variant disrupts the p.Arg124 amino acid residue in TGFBI. Other variant(s) that disrupt this residue have been determined to be pathogenic (Grothe HL, et al., 2013; Munier FL, et al., 2002). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant is reported with the allele frequency 0.004% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic. The amino acid Arginine at position 124 is changed to a Histidine changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The residue is conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 124 of the TGFBI protein (p.Arg124His). This variant is present in population databases (rs121909211, gnomAD 0.05%). This missense change has been observed in individuals with autosomal dominant corneal dystrophy (PMID: 11923233). ClinVar contains an entry for this variant (Variation ID: 7869). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TGFBI function (PMID: 26197481, 34097874). This variant disrupts the p.Arg124 amino acid residue in TGFBI. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10798644, 11923233, 23559853). 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:
Criteria applied: PS4,PM5_STR,PS3_MOD,PP3
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:
Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 22850414, PS3_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000007872, PMID:10425035,9054935,9780098, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.766, 3CNET: 0.902, PP3_P). A missense variant is a common mechanism associated with Corneal dystrophy (PP2_P). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
The observed missense variant c.371G>A(p.Arg124His) in the TGFBI gene has been reported previously in individual(s) with autosomal dominant corneal dystrophy (Nagano C, et al., 2019; Jozaei R, et al.,2022). Experimental studies have shown that this missense change affects TGFBI function (Nielsen NS, et al., 2021). This variant disrupts the p.Arg124 amino acid residue in TGFBI. Other variant(s) that disrupt this residue have been determined to be pathogenic (Grothe HL, et al., 2013; Munier FL, et al., 2002). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant is reported with the allele frequency 0.004% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic. The amino acid Arginine at position 124 is changed to a Histidine changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The residue is conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 124 of the TGFBI protein (p.Arg124His). This variant is present in population databases (rs121909211, gnomAD 0.05%). This missense change has been observed in individuals with autosomal dominant corneal dystrophy (PMID: 11923233). ClinVar contains an entry for this variant (Variation ID: 7869). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TGFBI function (PMID: 26197481, 34097874). This variant disrupts the p.Arg124 amino acid residue in TGFBI. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10798644, 11923233, 23559853). 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:
Criteria applied: PS4,PM5_STR,PS3_MOD,PP3
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Mutation-induced dimerization of transforming growth factor-β-induced protein may drive protein aggregation in granular corneal dystrophy. | Nielsen NS | The Journal of biological chemistry | 2021 | PMID: 34097874 |
| Development of a Transgenic Mouse with R124H Human TGFBI Mutation Associated with Granular Corneal Dystrophy Type 2. | Yamazoe K | PloS one | 2015 | PMID: 26197481 |
| Altered protein conformation and lower stability of the dystrophic transforming growth factor beta-induced protein mutants. | Grothe HL | Molecular vision | 2013 | PMID: 23559853 |
| In vitro amyloid aggregate forming ability of TGFBI mutants that cause corneal dystrophies. | Yam GH | Investigative ophthalmology & visual science | 2012 | PMID: 22850414 |
| An unusual clinical phenotype of Avellino corneal dystrophy associated with an Arg124His beta iG-H3 mutation in an African-American woman. | Meallet MA | American journal of ophthalmology | 2004 | PMID: 15059726 |
| BIGH3 mutation spectrum in corneal dystrophies. | Munier FL | Investigative ophthalmology & visual science | 2002 | PMID: 11923233 |
| BIGH3 exon 14 mutations lead to intermediate type I/IIIA of lattice corneal dystrophies. | Schmitt-Bernard CF | Investigative ophthalmology & visual science | 2000 | PMID: 10798644 |
| Heterogeneity in granular corneal dystrophy: identification of three causative mutations in the TGFBI (BIGH3) gene-lessons for corneal amyloidogenesis. | Stewart HS | Human mutation | 1999 | PMID: 10425035 |
| Kerato-epithelin mutations in four 5q31-linked corneal dystrophies. | Munier FL | Nature genetics | 1997 | PMID: 9054935 |
Text-mined citations for rs121909211 ...
HelpThese 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 08, 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.