This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. This variant alters a critical location within the protein, and is expected to severely affect function and cause disease.
ClinVar Genomic variation as it relates to human health
NM_033380.3(COL4A5):c.874G>A (p.Gly292Arg)
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.
(4)
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/Likely pathogenic
4
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_033380.3(COL4A5):c.874G>A (p.Gly292Arg)
Variation ID: 1076557 Accession: VCV001076557.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq22.3 X: 108580721 (GRCh38) [ NCBI UCSC ] X: 107823951 (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 May 10, 2021 Feb 28, 2024 Oct 11, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_033380.3:c.874G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_203699.1:p.Gly292Arg missense NM_000495.5:c.874G>A NP_000486.1:p.Gly292Arg missense NC_000023.11:g.108580721G>A NC_000023.10:g.107823951G>A NG_011977.2:g.145798G>A LRG_232:g.145798G>A LRG_232t1:c.874G>A LRG_232p1:p.Gly292Arg LRG_232t2:c.874G>A LRG_232p2:p.Gly292Arg - Protein change
- G292R
- Other names
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p.Gly292Arg
- Canonical SPDI
- NC_000023.11:108580720: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.
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- 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. |
|||
| COL4A5 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
2613 | 2795 | |
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/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Oct 11, 2023 | RCV001390504.11 |
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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|---|---|---|---|---|---|
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Pathogenic
(Jun 14, 2021)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV002771287.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Comment:
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features … (more)
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. This variant alters a critical location within the protein, and is expected to severely affect function and cause disease. (less)
|
|
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Pathogenic
(Dec 27, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV003921603.1
First in ClinVar: May 06, 2023 Last updated: May 06, 2023 |
Comment:
Reported in a family with Alport syndrome in published literature (Bekheirnia et al., 2010); Affects a glycine residue in a Gly-X-Y motif in the triple … (more)
Reported in a family with Alport syndrome in published literature (Bekheirnia et al., 2010); Affects a glycine residue in a Gly-X-Y motif in the triple helical region of the COL4A5 gene, where the majority of pathogenic missense variants occur, and is predicted to disrupt normal protein folding and function (HGMD; Jais et al., 2000); Not observed at significant frequency in large population cohorts (gnomAD); 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: 20378821, 10752524) (less)
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Likely pathogenic
(Oct 13, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004227694.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP3, PM1, PM2_supporting, PS4_moderate
Number of individuals with the variant: 1
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Pathogenic
(Oct 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001592244.4
First in ClinVar: May 10, 2021 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 292 of the COL4A5 protein (p.Gly292Arg). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 292 of the COL4A5 protein (p.Gly292Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with X-linked Alport syndrome (PMID: 20378821). ClinVar contains an entry for this variant (Variation ID: 1076557). 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 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). For these reasons, this variant has been classified as Pathogenic. (less)
|
Comment:
Comment:
Reported in a family with Alport syndrome in published literature (Bekheirnia et al., 2010); Affects a glycine residue in a Gly-X-Y motif in the triple helical region of the COL4A5 gene, where the majority of pathogenic missense variants occur, and is predicted to disrupt normal protein folding and function (HGMD; Jais et al., 2000); Not observed at significant frequency in large population cohorts (gnomAD); 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: 20378821, 10752524)
Comment:
PP3, PM1, PM2_supporting, PS4_moderate
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 292 of the COL4A5 protein (p.Gly292Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with X-linked Alport syndrome (PMID: 20378821). ClinVar contains an entry for this variant (Variation ID: 1076557). 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 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). For these reasons, this variant has been classified as Pathogenic.
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:
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. This variant alters a critical location within the protein, and is expected to severely affect function and cause disease.
Comment:
Reported in a family with Alport syndrome in published literature (Bekheirnia et al., 2010); Affects a glycine residue in a Gly-X-Y motif in the triple helical region of the COL4A5 gene, where the majority of pathogenic missense variants occur, and is predicted to disrupt normal protein folding and function (HGMD; Jais et al., 2000); Not observed at significant frequency in large population cohorts (gnomAD); 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: 20378821, 10752524)
Comment:
PP3, PM1, PM2_supporting, PS4_moderate
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 292 of the COL4A5 protein (p.Gly292Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with X-linked Alport syndrome (PMID: 20378821). ClinVar contains an entry for this variant (Variation ID: 1076557). 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 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). For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| X-Linked and Autosomal Recessive Alport Syndrome: Pathogenic Variant Features and Further Genotype-Phenotype Correlations. | Savige J | PloS one | 2016 | PMID: 27627812 |
| DNA variant databases improve test accuracy and phenotype prediction in Alport syndrome. | International Alport Mutation Consortium | Pediatric nephrology (Berlin, Germany) | 2014 | PMID: 23720012 |
| Genotype-phenotype correlation in X-linked Alport syndrome. | Bekheirnia MR | Journal of the American Society of Nephrology : JASN | 2010 | PMID: 20378821 |
| Collagen structure and stability. | Shoulders MD | Annual review of biochemistry | 2009 | PMID: 19344236 |
| Efficient detection of Alport syndrome COL4A5 mutations with multiplex genomic PCR-SSCP. | Barker DF | American journal of medical genetics | 2001 | PMID: 11223851 |
| 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 |
Text-mined citations for rs104886073 ...
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 Sep 29, 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.