ClinVar Genomic variation as it relates to human health
NM_000091.5(COL4A3):c.2083G>A (p.Gly695Arg)
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.
Pathogenic(6); Likely pathogenic(3); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000091.5(COL4A3):c.2083G>A (p.Gly695Arg)
Variation ID: 369964 Accession: VCV000369964.34
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q36.3 2: 227277511 (GRCh38) [ NCBI UCSC ] 2: 228142227 (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 Dec 24, 2018 Apr 15, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000091.5:c.2083G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000082.2:p.Gly695Arg missense NC_000002.12:g.227277511G>A NC_000002.11:g.228142227G>A NG_011591.1:g.117947G>A LRG_230:g.117947G>A LRG_230t1:c.2083G>A LRG_230p1:p.Gly695Arg - Protein change
- G695R
- Other names
- -
- Canonical SPDI
- NC_000002.12:227277510: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
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00011
Trans-Omics for Precision Medicine (TOPMed) 0.00014
Exome Aggregation Consortium (ExAC) 0.00016
The Genome Aggregation Database (gnomAD) 0.00016
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00017
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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COL4A3 | - | - |
GRCh38 GRCh37 |
24 | 2643 | |
MFF-DT | - | - | - | GRCh38 | - | 2526 |
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 (3) |
criteria provided, single submitter
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Mar 14, 2019 | RCV000408794.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 21, 2019 | RCV001001294.9 | |
Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Jan 31, 2024 | RCV001240936.13 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 17, 2022 | RCV001535934.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 30, 2023 | RCV002225103.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 12, 2016 | RCV002294326.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 8, 2022 | RCV002288979.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Mar 30, 2023 | RCV003226288.2 | |
COL4A3-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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Jan 3, 2024 | RCV003922661.1 |
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 21, 2019)
|
criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001158474.1
First in ClinVar: Feb 10, 2020 Last updated: Feb 10, 2020 |
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Pathogenic
(Mar 14, 2019)
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criteria provided, single submitter
Method: clinical testing
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Autosomal dominant Alport syndrome
Affected status: yes
Allele origin:
unknown
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Accession: SCV001427184.2
First in ClinVar: Aug 13, 2020 Last updated: Sep 18, 2020 |
Comment:
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease … (more)
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0104 - Dominant negative is a mechanism of disease for this gene. (N) 0108 - This gene is known to be associated with both recessive (Alport syndrome) and dominant (Alport syndrome and benign familial hematuria) disease (OMIM). (N) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine (exon 28). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 (31 heterozygotes, 0 homozygotes). (P) 0600 - Variant is located in an annotated motif (G-X-Y repeat in a triple helix motif; NCBI, PDB). (N) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0702 - Comparable variants have strong previous evidence for pathogenicity. Multiple substitutions of glycine in the G-X-Y motif within the collagen triple helix domain have been reported pathogenic (ClinVar). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been previously described as pathogenic and segregated with disease in families with either thin basement membrane nephropathy (TBMN) or autosomal recessive Alport syndrome (ARAS) (ClinVar; PMID: 30476138; PMID: 14871398; PMID: 29854973; PMID: 24130771; PMID: 24052634; PMID: 25229338; PMID: 23325022; PMID: 29098738). (P) 1206 - Variant is paternally inherited. However, it is suggested that carriers may present with milder symptoms (PMID: 30450445), which can potentially be difficult to diagnose (PMID: 28704582). (N) (less)
Clinical Features:
Hematuria (present) , Proteinuria (present)
Secondary finding: no
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Likely pathogenic
(Apr 08, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hematuria, benign familial, 1
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002581554.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PM1_STR, PM2_SUP, PM3_SUP, PP3
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Number of individuals with the variant: 1
Sex: female
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Uncertain significance
(Dec 12, 2016)
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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: SCV002587171.1
First in ClinVar: Oct 29, 2022 Last updated: Oct 29, 2022 |
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Pathogenic
(Apr 17, 2022)
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criteria provided, single submitter
Method: clinical testing
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Autosomal dominant Alport syndrome
Hematuria, benign familial, 1 Autosomal recessive Alport syndrome
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV001752592.2
First in ClinVar: Jul 18, 2021 Last updated: Dec 31, 2022 |
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Likely pathogenic
(Aug 12, 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: SCV001871253.3
First in ClinVar: Sep 19, 2021 Last updated: Mar 04, 2023 |
Comment:
Observed in multiple unrelated patients from different ethnic backgrounds with Alport syndrome and/or thin basement membrane nephropathy, and/or focal segmental glomerulosclerosis and hearing loss, and/or … (more)
Observed in multiple unrelated patients from different ethnic backgrounds with Alport syndrome and/or thin basement membrane nephropathy, and/or focal segmental glomerulosclerosis and hearing loss, and/or steroid-resistant nephrotic syndrome referred for genetic testing at GeneDx and in published literature (Wang et al., 2004; Chatterjee et al., 2013; Gale et al., 2013; Storey et al., 2013; Malone et al., 2014; Gillion et al., 2018; Varner et al., 2018); Affects a glycine residue in a Gly-X-Y motif in the triple helical region of the COL4A3 gene; 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: 24052634, 30406062, 30476138, 33635378, 25525159, 29854973, 26833262, 14871398, 24130771, 25229338, 23325022, 15880327, 29098738, 32647767, 31589614, 35177655, 34746741, 34883493, 34400539, 34662886, 33040356, 33654185, 32939031, 33712733) (less)
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Likely pathogenic
(Mar 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive Alport syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003922498.1
First in ClinVar: May 13, 2023 Last updated: May 13, 2023 |
Comment:
Variant summary: COL4A3 c.2083G>A (p.Gly695Arg) results in a non-conservative amino acid change in the encoded protein sequence that impacts a glycine residue in the collagenous … (more)
Variant summary: COL4A3 c.2083G>A (p.Gly695Arg) results in a non-conservative amino acid change in the encoded protein sequence that impacts a glycine residue in the collagenous domain of alpha 3 or alpha 4 collagen(IV). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 246794 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in COL4A3 causing Alport Syndrome, Autosomal Recessive (0.00011 vs 0.0014), allowing no conclusion about variant significance. c.2083G>A has been reported in the literature as heterozygous and compound heterozygous genotypes in individuals with features of Alport syndrome not limited to Focal Segmental Glomerulosclerosis (FSG), thin glomerular basement membrane, and IgA nephropathy (example, Storey_2013, Chatterjee_2013, Malone_2014, Gillion_2018, Daga_2014, Li_2020). Therefore, the possibility of a dominant or a recessive inheritance pattern attributed to this variant exists. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with a predominant consensus as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Pathogenic
(Jan 31, 2024)
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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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Invitae
Accession: SCV001413921.4
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 695 of the COL4A3 protein (p.Gly695Arg). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 695 of the COL4A3 protein (p.Gly695Arg). This variant is present in population databases (rs200287952, gnomAD 0.02%). This missense change has been observed in individuals with clinical features of Alport syndrome (PMID: 14871398, 24052634, 25229338, 29098738, 29854973; Invitae). ClinVar contains an entry for this variant (Variation ID: 369964). 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 COL4A3 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 03, 2024)
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criteria provided, single submitter
Method: clinical testing
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COL4A3-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004738859.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The COL4A3 c.2083G>A variant is predicted to result in the amino acid substitution p.Gly695Arg. This variant has been reported in both the heterozygous and compound … (more)
The COL4A3 c.2083G>A variant is predicted to result in the amino acid substitution p.Gly695Arg. This variant has been reported in both the heterozygous and compound heterozygous states in association with autosomal dominant and recessive COL4A3 related disorders (Wang et al. 2004. PubMed ID: 14871398; Storey et al. 2013. PubMed ID: 24052634; Chatterjee et al 2013. PubMed ID: 24130771; Malone et al. 2014. PubMed ID: 25229338; Boeckhaus et al. 2021. PubMed ID: 33040356). This variant has been observed to segregate with presumed autosomal dominant inheritance in a family with IgA nephropathy and in another family with hematuria and/or kidney failure (PED9 in Li et al. 2020. PubMed ID: 32647767; Gale, D. 2013. PubMed: 23325022). This variant is reported in 0.021% of alleles in individuals of European (Non-Finnish) descent in gnomAD. The p.Gly695 residue is located in the conserved triple helical domain, where substitutions of the glycine are usually pathogenic (UniProt residues 43-1438, Hudson et al. 1993. PubMed ID: 8253711; https://www.ncbi.nlm.nih.gov/books/NBK21582/). This variant is interpreted as pathogenic. (less)
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Pathogenic
(Mar 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Alport syndrome
Affected status: yes
Allele origin:
germline
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Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002503873.2
First in ClinVar: Apr 28, 2022 Last updated: Apr 15, 2024 |
Comment:
This sequence change is predicted to replace glycine with arginine at codon 695 of the COL4A3 protein, p.(Gly695Arg). The glycine residue is highly conserved (100 … (more)
This sequence change is predicted to replace glycine with arginine at codon 695 of the COL4A3 protein, p.(Gly695Arg). The glycine residue is highly conserved (100 vertebrates, UCSC), and there is a large physicochemical difference between glycine and arginine. The glycine residue is in a Gly-X-Y motif in the collagen triple helical region. The variant is present in a large population cohort at a frequency of 0.01%, which is consistent with a recessive condition (rs200287952, 31/278,152 alleles, 0 homozygotes in gnomAD v2.1). It has been identified compound heterozygous with a second pathogenic allele in at least one case with Alport syndrome (PMID: 24052634). Furthermore, the prevalence of the variant in individuals with moderate/severe haematuria is significantly increased compared with the prevalence in controls (PMID: 30476138), and segregates with thin basement membrane nephropathy in at least two families with autosomal dominant inheritance (PMID: 23325022, 25229338). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (7/7 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PS4, PM1, PM3, PP1_Moderate, PM2_Supporting, PP3. (less)
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Pathogenic
(Jun 14, 2018)
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no assertion criteria provided
Method: clinical testing
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Autosomal dominant Alport syndrome
Affected status: yes
Allele origin:
germline
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Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare
Accession: SCV000484947.2
First in ClinVar: Dec 18, 2016 Last updated: Dec 24, 2018 |
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Likely pathogenic
(Sep 01, 2020)
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no assertion criteria provided
Method: clinical testing
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Autosomal dominant Alport syndrome
Affected status: yes
Allele origin:
maternal
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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV001439344.1
First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020 |
Number of individuals with the variant: 2
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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: SCV001800179.1 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, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001931824.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 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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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001956097.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 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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Prevalence Estimates of Predicted Pathogenic COL4A3-COL4A5 Variants in a Population Sequencing Database and Their Implications for Alport Syndrome. | Gibson J | Journal of the American Society of Nephrology : JASN | 2021 | PMID: 34400539 |
Type IV Collagen Mutations in Familial IgA Nephropathy. | Li Y | Kidney international reports | 2020 | PMID: 32647767 |
Sequence variants associating with urinary biomarkers. | Benonisdottir S | Human molecular genetics | 2019 | PMID: 30476138 |
Genotype and Outcome After Kidney Transplantation in Alport Syndrome. | Gillion V | Kidney international reports | 2018 | PMID: 29854973 |
Urine-derived podocytes-lineage cells: A promising tool for precision medicine in Alport Syndrome. | Daga S | Human mutation | 2018 | PMID: 29098738 |
Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis. | Malone AF | Kidney international | 2014 | PMID: 25229338 |
Unbiased next generation sequencing analysis confirms the existence of autosomal dominant Alport syndrome in a relevant fraction of cases. | Fallerini C | Clinical genetics | 2014 | PMID: 24033287 |
Targeted exome sequencing integrated with clinicopathological information reveals novel and rare mutations in atypical, suspected and unknown cases of Alport syndrome or proteinuria. | Chatterjee R | PloS one | 2013 | PMID: 24130771 |
COL4A3/COL4A4 mutations and features in individuals with autosomal recessive Alport syndrome. | Storey H | Journal of the American Society of Nephrology : JASN | 2013 | PMID: 24052634 |
How benign is hematuria? Using genetics to predict prognosis. | Gale DP | Pediatric nephrology (Berlin, Germany) | 2013 | PMID: 23325022 |
COL4A3 mutations and their clinical consequences in thin basement membrane nephropathy (TBMN). | Wang YY | Kidney international | 2004 | PMID: 14871398 |
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Text-mined citations for rs200287952 ...
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.