ClinVar Genomic variation as it relates to human health
NM_000092.5(COL4A4):c.4394G>A (p.Gly1465Asp)
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(2); Likely pathogenic(2); Uncertain significance(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000092.5(COL4A4):c.4394G>A (p.Gly1465Asp)
Variation ID: 523324 Accession: VCV000523324.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q36.3 2: 227010441 (GRCh38) [ NCBI UCSC ] 2: 227875157 (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 12, 2018 Apr 15, 2024 Jan 23, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000092.5:c.4394G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000083.3:p.Gly1465Asp missense NC_000002.12:g.227010441C>T NC_000002.11:g.227875157C>T NG_011592.1:g.159119G>A LRG_231:g.159119G>A LRG_231t1:c.4394G>A LRG_231p1:p.Gly1465Asp - Protein change
- G1465D
- Other names
- p.Gly1465Asp
- Canonical SPDI
- NC_000002.12:227010440:C:T
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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.
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00007
Exome Aggregation Consortium (ExAC) 0.00009
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
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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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COL4A4 | - | - |
GRCh38 GRCh37 |
2841 | 2874 |
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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Likely pathogenic (1) |
criteria provided, single submitter
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Jan 1, 2017 | RCV000626596.2 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Apr 2, 2018 | RCV000673767.4 | |
Uncertain significance (2) |
criteria provided, single submitter
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Mar 30, 2023 | RCV001328187.3 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jan 23, 2024 | RCV001868162.5 | |
Pathogenic (1) |
criteria provided, single submitter
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May 4, 2022 | RCV002248830.1 |
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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Likely pathogenic
(Jan 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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Hearing impairment
Hematuria Hypertensive disorder Myopia Proteinuria
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000747297.1
First in ClinVar: May 12, 2018 Last updated: May 12, 2018 |
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Uncertain significance
(Apr 02, 2018)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive Alport syndrome
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000799008.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Pathogenic
(May 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hematuria, benign familial, 1
Affected status: unknown
Allele origin:
germline
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Mendelics
Accession: SCV002518752.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive Alport syndrome
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004048009.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
The missense c.4394G>A (p.Gly1465Asp) variant in COL4A4 gene has been reported in individual(s) with clinical features of autosomal dominant Alport syndrome and autosomal recessive Alport … (more)
The missense c.4394G>A (p.Gly1465Asp) variant in COL4A4 gene has been reported in individual(s) with clinical features of autosomal dominant Alport syndrome and autosomal recessive Alport syndrome (Fallerini, C et al.,2014; Papazachariou, L et al..2017). It has also been observed to segregate with disease in related individuals. This variant is reported with the allele frequency 0.006% in the gnomAD and novel in 1000 genome database. It has been submitted to ClinVar with varying interpretations: Likely Pathogenic/Uncertain Significance. The amino acid Gly at position 1465 is changed to a Asp changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Gly1465Asp in COL4A4 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. (less)
Clinical Features:
Renal insufficiency (present)
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Uncertain significance
(Jul 27, 2021)
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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: SCV004226007.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
BP2, PP3, PM2_supporting
Number of individuals with the variant: 1
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Pathogenic
(Jan 23, 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: SCV002306481.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1465 of the COL4A4 protein … (more)
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1465 of the COL4A4 protein (p.Gly1465Asp). This variant is present in population databases (rs533297350, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of autosomal dominant Alport syndrome, autosomal recessive Alport syndrome, and basement membrane disease (PMID: 24033287, 26934356, 28632965, 34584596). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 523324). 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 COL4A4 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. (less)
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Uncertain significance
(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: SCV002498602.2
First in ClinVar: Apr 11, 2022 Last updated: Apr 15, 2024 |
Comment:
This sequence change in COL4A4 is predicted to replace glycine with aspartic acid at codon 1465 (p.(Gly1465Asp)). The glycine residue is highly conserved (100 vertebrates, … (more)
This sequence change in COL4A4 is predicted to replace glycine with aspartic acid at codon 1465 (p.(Gly1465Asp)). The glycine residue is highly conserved (100 vertebrates, UCSC), and is located in the collagen IV NC1 domain. There is a moderate physicochemical difference between glycine and aspartic acid. The highest population minor allele frequency in gnomAD v2.1 is 0.04% (13/30,488 alleles) in the South Asian population, which is lower than the credible allele frequency for recessive Alport syndrome. This variant is almost always reported in cis with the likely pathogenic variant c.2320G>C, p.(Gly774Arg) in individuals and families with both dominant and recessive forms of Alport syndrome (PMID: 24033287, 26934356, 28632965, 29496980, 33048202, 33838161). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/5 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM2_Supporting, PP3. (less)
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Uncertain significance
(Jan 09, 2018)
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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: SCV001449267.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This individual is also homozygous for the c.4394G>A p.(Gly1465Asp) variant in the COL4A4 gene. To our knowledge, this variant has not been previously reported in … (more)
This individual is also homozygous for the c.4394G>A p.(Gly1465Asp) variant in the COL4A4 gene. To our knowledge, this variant has not been previously reported in the literature or any disease specific databases. The c.4394G>A variant has been reported in the gnomAD browser (http://gnomad.broadinstitute.org) with a very low allele frequency of 0.006% (19 out of 275976 alleles). In silico analysis of pathogenicity (through Alamut Visual v2.8.1) using PolyPhen2, SIFT and MutationTaster all suggest that this variant is likely to be pathogenic. This variant is considered to be a variant of uncertain clinical significance (VOUS) according to the ACMG guidelines. (less)
Number of individuals with the variant: 1
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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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Neuroendocrine pancreatic tumor in a patient with dual diagnosis of tuberous sclerosis complex and basement membrane disease: A case report and review of the literature. | Kopadze S | Radiology case reports | 2021 | PMID: 34584596 |
Clinical and Genetic Features of Autosomal Dominant Alport Syndrome: A Cohort Study. | Furlano M | American journal of kidney diseases : the official journal of the National Kidney Foundation | 2021 | PMID: 33838161 |
Long-term outcome among females with Alport syndrome from a single pediatric center. | Goka S | Pediatric nephrology (Berlin, Germany) | 2021 | PMID: 33048202 |
Dominant ELOVL1 mutation causes neurological disorder with ichthyotic keratoderma, spasticity, hypomyelination and dysmorphic features. | Kutkowska-Kaźmierczak A | Journal of medical genetics | 2018 | PMID: 29496980 |
Frequent COL4 mutations in familial microhematuria accompanied by later-onset Alport nephropathy due to focal segmental glomerulosclerosis. | Papazachariou L | Clinical genetics | 2017 | PMID: 28632965 |
Efficient Targeted Next Generation Sequencing-Based Workflow for Differential Diagnosis of Alport-Related Disorders. | Kovács G | PloS one | 2016 | PMID: 26934356 |
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 |
Text-mined citations for rs533297350 ...
HelpRecord last updated Apr 20, 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.