ClinVar Genomic variation as it relates to human health
NM_033380.3(COL4A5):c.4808A>G (p.Tyr1603Cys)
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.4808A>G (p.Tyr1603Cys)
Variation ID: 1803954 Accession: VCV001803954.4
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq22.3 X: 108694908 (GRCh38) [ NCBI UCSC ] X: 107938138 (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 Dec 24, 2022 Feb 14, 2024 Mar 10, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_033380.3:c.4808A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_203699.1:p.Tyr1603Cys missense NM_000495.5:c.4790A>G NP_000486.1:p.Tyr1597Cys missense NC_000023.11:g.108694908A>G NC_000023.10:g.107938138A>G NG_011977.2:g.259985A>G LRG_232:g.259985A>G LRG_232t1:c.4790A>G LRG_232p1:p.Tyr1597Cys LRG_232t2:c.4808A>G LRG_232p2:p.Tyr1603Cys - Protein change
- Y1597C, Y1603C
- Other names
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- Canonical SPDI
- NC_000023.11:108694907:A:G
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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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- Links
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 |
- | 2667 |
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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Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Sep 7, 2021 | RCV002468692.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Mar 10, 2023 | RCV002569361.2 |
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
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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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Likely pathogenic
(Sep 07, 2021)
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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: SCV002764655.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Number of individuals with the variant: 1
Clinical Features:
Focal segmental glomerulosclerosis (present)
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Likely pathogenic
(May 06, 2021)
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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: SCV002767321.1
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 Likely Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely 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 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, PMID: 12028435). (I) 0110 - This gene is associated with X-linked dominant disease. Males are typically more severely affected than females (PMID: 19965530). (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to cysteine. (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 and highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants in the C4 domain (DECIPHER, NCBI). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported as pathogenic in at least three individuals with X-linked Alport syndrome 1 (MIM#301050), and is sometimes annotated using an alternate transcript (NM_000495.3(PKD1):c.4790A>G;p.(Tyr1597Cys)) (ClinVar, HGMD, LOVD, PMID: 8887300, PMID: 12105244). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1102 - Strong phenotype match for this individual. (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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Likely pathogenic
(Mar 10, 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: SCV003445837.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has … (more)
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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: 1803954). This variant is also known as A4992>G. This missense change has been observed in individuals with clinical features of Alport syndrome (PMID: 12105244; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1597 of the COL4A5 protein (p.Tyr1597Cys). (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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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 |
Meta-analysis of genotype-phenotype correlation in X-linked Alport syndrome: impact on clinical counselling. | Gross O | Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association | 2002 | PMID: 12105244 |
COL4A3/COL4A4 mutations: from familial hematuria to autosomal-dominant or recessive Alport syndrome. | Longo I | Kidney international | 2002 | PMID: 12028435 |
Use of psoralen-coupled nucleotide primers for screening of COL4A5 mutations in Alport syndrome. | Netzer KO | Kidney international | 1996 | PMID: 8887300 |
Text-mined citations for rs104886298 ...
HelpRecord last updated Mar 05, 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.