ClinVar Genomic variation as it relates to human health
NM_033380.3(COL4A5):c.2605G>A (p.Gly869Arg)
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_033380.3(COL4A5):c.2605G>A (p.Gly869Arg)
Variation ID: 24543 Accession: VCV000024543.24
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq22.3 X: 108620354 (GRCh38) [ NCBI UCSC ] X: 107863584 (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 Jul 15, 2024 Apr 23, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_033380.3:c.2605G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_203699.1:p.Gly869Arg missense NM_000495.5:c.2605G>A NP_000486.1:p.Gly869Arg missense NC_000023.11:g.108620354G>A NC_000023.10:g.107863584G>A NG_011977.2:g.185431G>A LRG_232:g.185431G>A LRG_232t1:c.2605G>A LRG_232p1:p.Gly869Arg LRG_232t2:c.2605G>A LRG_232p2:p.Gly869Arg P29400:p.Gly869Arg - Protein change
- G869R
- Other names
- p.G869R
- Canonical SPDI
- NC_000023.11:108620353: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
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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COL4A5 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
2568 | 2749 |
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/Likely pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Apr 23, 2024 | RCV000021422.14 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 17, 2023 | RCV000311568.7 | |
Pathogenic (1) |
no assertion criteria provided
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Oct 25, 2018 | RCV001328145.2 | |
Pathogenic (1) |
no assertion criteria provided
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Sep 13, 2019 | RCV001328141.2 | |
Pathogenic (1) |
no assertion criteria provided
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Feb 14, 2019 | RCV001849275.2 |
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
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 02, 2016)
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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: SCV000329767.6
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Comment:
The G869R pathogenic variant in the COL4A5 gene has been reported previously in multiple unrelated individuals with X-linked Alport syndrome (Boye et al., 1995; Knebelman … (more)
The G869R pathogenic variant in the COL4A5 gene has been reported previously in multiple unrelated individuals with X-linked Alport syndrome (Boye et al., 1995; Knebelman et al., 1996; Plant et al., 1999). The G869R variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G869R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret G869R as a pathogenic variant. (less)
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Likely pathogenic
(Dec 03, 2018)
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criteria provided, single submitter
Method: research
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X-linked Alport syndrome
(X-linked inheritance)
Affected status: yes
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001164380.1
First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020 |
Comment:
The hemizygous p.Gly869Arg variant in COL4A5 was identified by our study in one individual with X-linked Alport syndrome. This variant was absent from large population … (more)
The hemizygous p.Gly869Arg variant in COL4A5 was identified by our study in one individual with X-linked Alport syndrome. This variant was absent from large population studies and computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Trio exome analysis showed this variant to be de novo in one individual reported in the literature (PMID: 8940267). The p.Gly869Arg variant in COL4A5 has been reported in ten additional individuals with Alport syndrome (PMID: 8651296, 7599631, 9848783). This variant has also been reported pathogenic in ClinVar (Variation ID: 24543). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM6, PP3 (Richards 2015). (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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X-linked Alport syndrome
(X-linked inheritance)
Affected status: yes
Allele origin:
germline
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Watson Genetic Lab
Accession: SCV005046906.1
First in ClinVar: Jun 09, 2024 Last updated: Jun 09, 2024 |
Sex: male
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Pathogenic
(Jan 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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X-linked Alport syndrome
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002059127.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000024543, PS1_S). A different … (more)
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000024543, PS1_S). A different missense change at the same codon has been reported to be associated with COL4A5 related disorder (ClinVar ID: VCV000807394, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.978, 3CNET: 0.973, PP3_P). A missense variant is a common mechanism associated with Alport syndrome 1 (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). 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:
Bulbous nose (present) , Epicanthus (present) , Periorbital hyperpigmentation (present) , Macroscopic hematuria (present) , Micrognathia (present) , Proportionate short stature (present)
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Pathogenic
(Dec 05, 2017)
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criteria provided, single submitter
Method: clinical testing
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Alport syndrome, X-linked recessive
Affected status: yes
Allele origin:
germline
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Center of Genomic medicine, Geneva, University Hospital of Geneva
Accession: SCV000747762.2
First in ClinVar: Apr 04, 2013 Last updated: Dec 11, 2022 |
Age: 30-39 years
Sex: female
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Pathogenic
(Mar 31, 2022)
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criteria provided, single submitter
Method: clinical testing
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X-linked Alport syndrome
(X-linked dominant inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002767917.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative, caused by missense variants mostly … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative, caused by missense variants mostly glycine substitutions that affect the conformation of the protein, and loss of function, caused by either protein truncating or missense variants, are known mechanisms of disease in this gene and are associated with Alport syndrome (MIM#301050) (PMIDs: 24046192, 12028435). (I) 0110 - This gene is associated with X-linked dominant disease, with males usually affected more severely than females (PMID: 19965530). (I) 0115 - Variants in this gene are known to have variable expressivity. There is intrafamilial variability among affected carrier females, possibly due to variable X-inactivation (PMID: 14514738). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the well-established triple helical G-X-Y repeat region, and affects a glycine residue (DECIPHER). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Gly869Val) has been previously reported as pathogenic by a clinical laboratory in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported several times as pathogenic, and has been observed in many hemizygous or heterozygous individuals with Alport syndrome (ClinVar, PMIDs: 27627812, 23144074). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Jul 23, 2021)
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criteria provided, single submitter
Method: clinical testing
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X-linked Alport syndrome
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002806615.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Aug 17, 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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Invitae
Accession: SCV001214001.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the triple helix domain of COL4A5. Glycine residues within the Gly-Xaa-Yaa repeats … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the triple helix domain of COL4A5. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). In COL4A5, missense variants at these glycine residues are significantly enriched in individuals with disease (PMID: 23720012, 27627812) compared to the general population (ExAC). 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 COL4A5 protein function. ClinVar contains an entry for this variant (Variation ID: 24543). This variant is also known as c.2808G>A. This missense change has been observed in individuals with Alport syndrome (PMID: 7599631, 30577881). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 869 of the COL4A5 protein (p.Gly869Arg). (less)
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Pathogenic
(Apr 23, 2024)
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criteria provided, single submitter
Method: clinical testing
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X-linked Alport syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005077015.1
First in ClinVar: Jul 15, 2024 Last updated: Jul 15, 2024 |
Comment:
Variant summary: COL4A5 c.2605G>A (p.Gly869Arg) results in a non-conservative amino acid change located within the triple-helical region (UniProt) of the encoded protein sequence. This missense … (more)
Variant summary: COL4A5 c.2605G>A (p.Gly869Arg) results in a non-conservative amino acid change located within the triple-helical region (UniProt) of the encoded protein sequence. This missense variant disrupts a critical glycine residue at position 1 of a Gly-X-Y repeat in the collagenous domain of the collagen IV alpha 5 chain, and variants affecting these glycine residues are significantly enriched in individuals with Alport syndrome (PMID: 33854215). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 182139 control chromosomes. c.2605G>A has been reported in the literature in individuals affected with Alport Syndrome 1, X-Linked Recessive (example, Connaughton_2019, Hashimura_2014, Ma_2011). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30773290, 24304881, 21505094). ClinVar contains an entry for this variant (Variation ID: 24543). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jan 09, 2018)
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no assertion criteria provided
Method: clinical testing
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X-linked Alport syndrome
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002083648.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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Pathogenic
(Sep 13, 2019)
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no assertion criteria provided
Method: clinical testing
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Alport syndrome
Affected status: yes
Allele origin:
unknown
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Sydney Genome Diagnostics, Children's Hospital Westmead
Accession: SCV001449304.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This individual is heterozygous for the c.2605G>A variant in the COL4A5 gene, which results in the amino acid substitution of glycine to arginine at residue … (more)
This individual is heterozygous for the c.2605G>A variant in the COL4A5 gene, which results in the amino acid substitution of glycine to arginine at residue 869, p.(Gly869Arg). This substitution affects one of the invariant glycine residues within the triple helical domain. This variant has been reported in numerous individuals with Alport syndrome (Knebelmann B et al 1996 Am J Hum Genet 59: 1221-1232; Ma et al 2011 Nephrol Dial Transplant 26: 4003-4010; Strasser et al 2012 Nephrol Dial Transplant 27: 4236-4240; Alport (COL4A5) Database: http://www.arup.utah.edu/database/ALPORT/ALPORT_display.php). The c.2605G>A variant has not been reported in any population databases (i.e. gnomAD, ExAC, ESP or dbSNP). This variant is considered to be pathogenic according to the ACMG guidelines (Evidence used: PM1_Strong, PS4). (less)
Number of individuals with the variant: 2
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Pathogenic
(Oct 25, 2018)
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no assertion criteria provided
Method: clinical testing
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Atypical hemolytic-uremic syndrome
Affected status: yes
Allele origin:
unknown
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Sydney Genome Diagnostics, Children's Hospital Westmead
Accession: SCV001449309.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This patient is hemizygous for the c.2605G>A (p.Gly869Arg) variant in the COL4A5 gene. This variant has been reported to be associated with Alport syndrome (Strasser … (more)
This patient is hemizygous for the c.2605G>A (p.Gly869Arg) variant in the COL4A5 gene. This variant has been reported to be associated with Alport syndrome (Strasser et al Nephrol Dial Transplant (2012) 27: 4236-4240). In silico analysis (Alamutv2.4) using Align GVGD, PolyPhen2, SIFT and Mutation taster all predict that this variant is likely to be pathogenic. In addition, p.Gly869 is a highly conserved amino acid within the triple helix domain. Glycine residues, in this domain, are important for the steric arrangement of the collagen chains (Knebelmann B et al. Am J Hum Genet 1996; 59: 1221-1232). (less)
Number of individuals with the variant: 1
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Pathogenic
(Feb 14, 2019)
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no assertion criteria provided
Method: literature only
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Autosomal dominant Alport syndrome
Affected status: yes
Allele origin:
germline
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Yale Center for Mendelian Genomics, Yale University
Study: Yale Center for Mendelian Genomics
Accession: SCV002106604.1 First in ClinVar: Mar 28, 2022 Last updated: Mar 28, 2022 |
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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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Monogenic causes of chronic kidney disease in adults. | Connaughton DM | Kidney international | 2019 | PMID: 30773290 |
X-linked Alport syndrome: pathogenic variant features and further auditory genotype-phenotype correlations in males. | Zhang X | Orphanet journal of rare diseases | 2018 | PMID: 30577881 |
X-Linked and Autosomal Recessive Alport Syndrome: Pathogenic Variant Features and Further Genotype-Phenotype Correlations. | Savige J | PloS one | 2016 | PMID: 27627812 |
Milder clinical aspects of X-linked Alport syndrome in men positive for the collagen IV α5 chain. | Hashimura Y | Kidney international | 2014 | PMID: 24304881 |
DNA variant databases improve test accuracy and phenotype prediction in Alport syndrome. | International Alport Mutation Consortium | Pediatric nephrology (Berlin, Germany) | 2014 | PMID: 23720012 |
Molecular genetics of familial hematuric diseases. | Deltas C | Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association | 2013 | PMID: 24046192 |
COL4A5-associated X-linked Alport syndrome in a female patient with early inner ear deafness due to a mutation in MYH9. | Strasser K | Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association | 2012 | PMID: 23144074 |
Twenty-one novel mutations identified in the COL4A5 gene in Chinese patients with X-linked Alport's syndrome confirmed by skin biopsy. | Ma J | Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association | 2011 | PMID: 21505094 |
Alport retinopathy results from "severe" COL4A5 mutations and predicts early renal failure. | Tan R | Clinical journal of the American Society of Nephrology : CJASN | 2010 | PMID: 19965530 |
Collagen structure and stability. | Shoulders MD | Annual review of biochemistry | 2009 | PMID: 19344236 |
X-linked Alport syndrome: natural history and genotype-phenotype correlations in girls and women belonging to 195 families: a "European Community Alport Syndrome Concerted Action" study. | Jais JP | Journal of the American Society of Nephrology : JASN | 2003 | PMID: 14514738 |
COL4A3/COL4A4 mutations: from familial hematuria to autosomal-dominant or recessive Alport syndrome. | Longo I | Kidney international | 2002 | PMID: 12028435 |
High mutation detection rate in the COL4A5 collagen gene in suspected Alport syndrome using PCR and direct DNA sequencing. | Martin P | Journal of the American Society of Nephrology : JASN | 1998 | PMID: 9848783 |
Spectrum of mutations in the COL4A5 collagen gene in X-linked Alport syndrome. | Knebelmann B | American journal of human genetics | 1996 | PMID: 8940267 |
X-linked Alport syndrome: an SSCP-based mutation survey over all 51 exons of the COL4A5 gene. | Renieri A | American journal of human genetics | 1996 | PMID: 8651296 |
Detection of 12 novel mutations in the collagenous domain of the COL4A5 gene in Alport syndrome patients. | Boye E | Human mutation | 1995 | PMID: 7599631 |
Crystal and molecular structure of a collagen-like peptide at 1.9 A resolution. | Bella J | Science (New York, N.Y.) | 1994 | PMID: 7695699 |
Characterization of collagen-like peptides containing interruptions in the repeating Gly-X-Y sequence. | Long CG | Biochemistry | 1993 | PMID: 8218237 |
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Text-mined citations for rs104886189 ...
HelpRecord last updated Jul 23, 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.