ClinVar Genomic variation as it relates to human health
NM_000091.5(COL4A3):c.1216C>T (p.Arg406Ter)
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_000091.5(COL4A3):c.1216C>T (p.Arg406Ter)
Variation ID: 495548 Accession: VCV000495548.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q36.3 2: 227263845 (GRCh38) [ NCBI UCSC ] 2: 228128561 (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 Mar 17, 2018 Feb 14, 2024 Jan 5, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000091.5:c.1216C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000082.2:p.Arg406Ter nonsense NC_000002.12:g.227263845C>T NC_000002.11:g.228128561C>T NG_011591.1:g.104281C>T LRG_230:g.104281C>T LRG_230t1:c.1216C>T LRG_230p1:p.Arg406Ter - Protein change
- R406*
- Other names
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- Canonical SPDI
- NC_000002.12:227263844: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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD) 0.00005
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
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
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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 (3) |
criteria provided, multiple submitters, no conflicts
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Jun 26, 2016 | RCV000589718.5 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 5, 2024 | RCV001046549.12 | |
Pathogenic (1) |
no assertion criteria provided
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Sep 16, 2020 | RCV001272227.1 |
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 26, 2016)
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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: SCV000695382.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The COL4A3 c.1216C>T (p.Arg406X) variant causes a premature termination codon, predicted to cause a truncated or absent COL4A3 protein due to nonsense mediated … (more)
Variant summary: The COL4A3 c.1216C>T (p.Arg406X) variant causes a premature termination codon, predicted to cause a truncated or absent COL4A3 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant of interest was not observed in controls (ExAC, 1000 Gs or ESP) and has been reported in an affected individual, who was homozygous for the variant (Heidet_2001). Therefore, taking all the available lines of evidence into consideration, the variant of interest has been classified as Pathogenic. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive Alport syndrome
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV002073112.1
First in ClinVar: Feb 03, 2022 Last updated: Feb 03, 2022 |
Comment:
The stop gained p.R406* in COL4A3 (NM_000091.5) has been previously reported in multiple affected individuals (Heidet L et al; Yamamura T et al). The variant … (more)
The stop gained p.R406* in COL4A3 (NM_000091.5) has been previously reported in multiple affected individuals (Heidet L et al; Yamamura T et al). The variant has been submiited to ClinVar as Pathogenic. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been reported previously to be disease causing. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Nephrotic syndrome (present) , Grade IV vesicoureteral reflux (present) , Recurrent urinary tract infections (present) , Hydronephrosis (present)
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Pathogenic
(Sep 08, 2023)
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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: SCV002540314.4
First in ClinVar: Jul 08, 2022 Last updated: Sep 14, 2023 |
Comment:
Reported phase unknown with a second COL4A3 variant in a patient with hearing loss in the literature (Horinouchi et al., 2020); Reported in a patient … (more)
Reported phase unknown with a second COL4A3 variant in a patient with hearing loss in the literature (Horinouchi et al., 2020); Reported in a patient with Alport syndrome who also harbored a COL4A5 deletion in published literature (Yamamura et al., 2017); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 11134255, 29270492, Lee_2022_Article, 33772369, 35369551, 35675912) (less)
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Pathogenic
(Jan 05, 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: SCV001210454.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg406*) in the COL4A3 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg406*) in the COL4A3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL4A3 are known to be pathogenic (PMID: 8956999, 24854265, 26809805, 27281700). This variant is present in population databases (no rsID available, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with end stage renal disease or Alport syndrome (PMID: 11134255, 29270492). ClinVar contains an entry for this variant (Variation ID: 495548). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Aug 23, 2017)
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no assertion criteria provided
Method: clinical testing
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Autosomal recessive Alport syndrome
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000793366.2
First in ClinVar: Mar 17, 2018 Last updated: Dec 23, 2019 |
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Alport syndrome
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001454010.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 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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Natural History and Genotype-Phenotype Correlation in Female X-Linked Alport Syndrome. | Yamamura T | Kidney international reports | 2017 | PMID: 29270492 |
Genetic, Clinical, and Pathologic Backgrounds of Patients with Autosomal Dominant Alport Syndrome. | Kamiyoshi N | Clinical journal of the American Society of Nephrology : CJASN | 2016 | PMID: 27281700 |
Identification of 47 novel mutations in patients with Alport syndrome and thin basement membrane nephropathy. | Weber S | Pediatric nephrology (Berlin, Germany) | 2016 | PMID: 26809805 |
Improving mutation screening in familial hematuric nephropathies through next generation sequencing. | Morinière V | Journal of the American Society of Nephrology : JASN | 2014 | PMID: 24854265 |
Structure of the human type IV collagen gene COL4A3 and mutations in autosomal Alport syndrome. | Heidet L | Journal of the American Society of Nephrology : JASN | 2001 | PMID: 11134255 |
Collagen COL4A3 knockout: a mouse model for autosomal Alport syndrome. | Cosgrove D | Genes & development | 1996 | PMID: 8956999 |
Text-mined citations for rs371334239 ...
HelpRecord last updated Apr 06, 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.