ClinVar Genomic variation as it relates to human health
NM_033380.3(COL4A5):c.973G>A (p.Gly325Arg)
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.973G>A (p.Gly325Arg)
Variation ID: 24352 Accession: VCV000024352.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq22.3 X: 108582920 (GRCh38) [ NCBI UCSC ] X: 107826150 (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 Aug 11, 2024 May 14, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_033380.3:c.973G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_203699.1:p.Gly325Arg missense NM_000495.5:c.973G>A NP_000486.1:p.Gly325Arg missense NM_033380.2:c.973G>A NC_000023.11:g.108582920G>A NC_000023.10:g.107826150G>A NG_011977.2:g.147997G>A LRG_232:g.147997G>A LRG_232t1:c.973G>A LRG_232p1:p.Gly325Arg LRG_232t2:c.973G>A LRG_232p2:p.Gly325Arg P29400:p.Gly325Arg - Protein change
- G325R
- Other names
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- Canonical SPDI
- NC_000023.11:108582919: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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COL4A5 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
2582 | 2763 |
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 (4) |
criteria provided, multiple submitters, no conflicts
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Dec 21, 2023 | RCV000011205.13 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 22, 2023 | RCV000521446.5 | |
Pathogenic (1) |
criteria provided, single submitter
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May 14, 2024 | RCV004609294.1 |
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
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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
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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
(May 10, 2019)
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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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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV001149731.1
First in ClinVar: Feb 03, 2020 Last updated: Feb 03, 2020 |
Sex: male
Tissue: blood
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Pathogenic
(Dec 04, 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: SCV002807814.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Aug 22, 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: SCV001591116.4
First in ClinVar: May 10, 2021 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. This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 325 of the COL4A5 protein (p.Gly325Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Alport syndrome (PMID: 1376965, 24472419). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 24352). (less)
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Pathogenic
(May 14, 2024)
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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: SCV005106024.1
First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024 |
Comment:
The c.973G>A (p.G325R) alteration is located in exon 17 (coding exon 17) of the COL4A5 gene. This alteration results from a G to A substitution … (more)
The c.973G>A (p.G325R) alteration is located in exon 17 (coding exon 17) of the COL4A5 gene. This alteration results from a G to A substitution at nucleotide position 973, causing the glycine (G) at amino acid position 325 to be replaced by an arginine (R). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported in multiple individuals with features consistent with COL4A5-related Alport syndrome and shown to segregate with disease in an affected family (Knebelmann, 1992; Wang, 2005; Gast, 2016). Another alteration at the same codon, c.974G>A (p.G325E), has been determined to be the result of a de novo mutation in one individual with features consistent with COL4A5-related Alport syndrome (Renieri, 1992). This amino acid position is highly conserved in available vertebrate species. The p.G325R amino acid is located within the triple-helical domain of the collagen alpha-5(IV) chain, and affects one of the highly conserved glycine residues in the Gly-X-Y motif that make up this domain (Ramshaw, 1998). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
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Pathogenic
(Aug 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000616682.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
Comment:
The G325R variant has been published previously in association with Alport syndrome (Knebelmann et al., 1992; Barker et al., 2001). The variant is not observed … (more)
The G325R variant has been published previously in association with Alport syndrome (Knebelmann et al., 1992; Barker et al., 2001). The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). G325R 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. G325R occurs in the triple helical domain and replaces the Glycine in the canonical Gly-X-Y repeat. Variants in these Glycines result in poor winding of the collagen triple helix and a less functional protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same residue (G325E) and in nearby residues (G310R/E, G313S/V, G316D, G319R/V/D, G322D/V, G331V, G334S/V, G337S), as well as a different nucleotide change leading to the same missense variant, c.973 G>C, have been reported in the Human Gene Mutation Database in association with Alport syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, we consider this variant to be pathogenic. (less)
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Pathogenic
(Dec 21, 2023)
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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: SCV005086652.1
First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with X-linked Alport syndrome 1 (MIM#301050). Dominant negative is caused mostly by glycine substitutions that affect the conformation of the protein, and loss of function can be caused by either protein truncating or missense variants (PMID: 24046192, 12028435). (I) 0110 - This gene is associated with X-linked dominant disease. Males are typically more severely affected 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) 0253 - This variant is hemizygous. (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 functional Gly-X-Y motif in the collagen triple helical domain. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant, along with an alternative nucleotide change (c.973G>C) resulting in the same amino acid substitution, has been reported in at least six individuals with Alport syndrome (ClinVar, PMIDs: 1376965, 17396119, VCGS). (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 01, 1992)
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no assertion criteria provided
Method: literature only
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ALPORT SYNDROME 1, X-LINKED
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000031432.2
First in ClinVar: Apr 04, 2013 Last updated: Feb 04, 2019 |
Comment on evidence:
In a kindred with many members affected with adult-type X-linked Alport syndrome (ALS1; 301050), Knebelmann et al. (1992) found by Southern blot analysis a loss … (more)
In a kindred with many members affected with adult-type X-linked Alport syndrome (ALS1; 301050), Knebelmann et al. (1992) found by Southern blot analysis a loss of an MspI restriction site in the COL4A5 gene. Direct sequencing of cDNA demonstrated a gly325-to-arg (G325R) mutation. Knebelmann et al. (1992) commented that this type of mutation in the COL1A1 and COL1A2 genes is often associated with osteogenesis imperfecta. (less)
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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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X-Linked and Autosomal Recessive Alport Syndrome: Pathogenic Variant Features and Further Genotype-Phenotype Correlations. | Savige J | PloS one | 2016 | PMID: 27627812 |
Collagen (COL4A) mutations are the most frequent mutations underlying adult focal segmental glomerulosclerosis. | Gast C | Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association | 2016 | PMID: 26346198 |
DNA variant databases improve test accuracy and phenotype prediction in Alport syndrome. | International Alport Mutation Consortium | Pediatric nephrology (Berlin, Germany) | 2014 | PMID: 23720012 |
Exome analysis resolves differential diagnosis of familial kidney disease and uncovers a potential confounding variant. | Gibson J | Genetics research | 2013 | PMID: 24472419 |
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 |
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 |
Sixteen novel mutations identified in COL4A3, COL4A4, and COL4A5 genes in Slovenian families with Alport syndrome and benign familial hematuria. | Slajpah M | Kidney international | 2007 | PMID: 17396119 |
Detection of mutations in the COL4A5 gene by analyzing cDNA of skin fibroblasts. | Wang F | Kidney international | 2005 | PMID: 15780079 |
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 |
Gly-X-Y tripeptide frequencies in collagen: a context for host-guest triple-helical peptides. | Ramshaw JA | Journal of structural biology | 1998 | PMID: 9724608 |
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 |
Substitution of arginine for glycine 325 in the collagen alpha 5 (IV) chain associated with X-linked Alport syndrome: characterization of the mutation by direct sequencing of PCR-amplified lymphoblast cDNA fragments. | Knebelmann B | American journal of human genetics | 1992 | PMID: 1376965 |
De novo mutation in the COL4A5 gene converting glycine 325 to glutamic acid in Alport syndrome. | Renieri A | Human molecular genetics | 1992 | PMID: 1363780 |
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Text-mined citations for rs104886088 ...
HelpRecord last updated Aug 11, 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.