ACMG Criteria: PP3_STR,PM5,PM1_SUP,PM2_SUP,PP4
ClinVar Genomic variation as it relates to human health
NM_033380.3(COL4A5):c.4912T>C (p.Cys1638Arg)
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.
(2)
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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
2
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.4912T>C (p.Cys1638Arg)
Variation ID: 3236356 Accession: VCV003236356.2
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq22.3 X: 108695357 (GRCh38) [ NCBI UCSC ] X: 107938587 (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 27, 2024 Jul 23, 2024 Mar 7, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_033380.3:c.4912T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_203699.1:p.Cys1638Arg missense NM_000495.5:c.4894T>C NP_000486.1:p.Cys1632Arg missense NM_033380.2:c.4912T>C NC_000023.11:g.108695357T>C NC_000023.10:g.107938587T>C NG_011977.2:g.260434T>C LRG_232:g.260434T>C LRG_232t1:c.4894T>C LRG_232p1:p.Cys1632Arg LRG_232t2:c.4912T>C LRG_232p2:p.Cys1638Arg - Protein change
- C1632R, C1638R
- Other names
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- Canonical SPDI
- NC_000023.11:108695356:T:C
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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
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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
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. |
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| COL4A5 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
2615 | 2797 | |
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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| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Mar 7, 2024 | RCV004555732.3 |
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
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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
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
(Mar 07, 2024)
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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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MVZ Medizinische Genetik Mainz
Accession: SCV005044685.1
First in ClinVar: May 26, 2024 Last updated: May 26, 2024 |
Comment:
ACMG Criteria: PP3_STR,PM5,PM1_SUP,PM2_SUP,PP4
Number of individuals with the variant: 1
Clinical Features:
Focal segmental glomerulosclerosis (present) , Kidney disorder (present) , Hypertensive disorder (present) , Microangiopathic hemolytic anemia (present) , Global glomerulosclerosis (present)
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Pathogenic
(Jul 17, 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: SCV005086595.1
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 cysteine to arginine. (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 or highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the well-established functional C4 domain (DECIPHER, PMID: 36721056). (SP) 0702 - Other variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Other amino acid changes at the same position, p.(Cys1638Ser) , p.(Cys1638Tyr) and (Cys1638Trp), have been reported as pathogenic/likely pathogenic in individuals with Alport syndrome (ClinVar, PMID: 24033287, PMID: 26809805, PMID: 17277342). (SP) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant was reported as pathogenic in PMID: 35789182, citing LOVD as the source. However, the variant is not currently listed in LOVD and therefore, there is uncertainty regarding this classification. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 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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Comment:
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 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 cysteine to arginine. (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 or highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the well-established functional C4 domain (DECIPHER, PMID: 36721056). (SP) 0702 - Other variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Other amino acid changes at the same position, p.(Cys1638Ser) , p.(Cys1638Tyr) and (Cys1638Trp), have been reported as pathogenic/likely pathogenic in individuals with Alport syndrome (ClinVar, PMID: 24033287, PMID: 26809805, PMID: 17277342). (SP) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant was reported as pathogenic in PMID: 35789182, citing LOVD as the source. However, the variant is not currently listed in LOVD and therefore, there is uncertainty regarding this classification. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
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:
ACMG Criteria: PP3_STR,PM5,PM1_SUP,PM2_SUP,PP4
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 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 cysteine to arginine. (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 or highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the well-established functional C4 domain (DECIPHER, PMID: 36721056). (SP) 0702 - Other variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Other amino acid changes at the same position, p.(Cys1638Ser) , p.(Cys1638Tyr) and (Cys1638Trp), have been reported as pathogenic/likely pathogenic in individuals with Alport syndrome (ClinVar, PMID: 24033287, PMID: 26809805, PMID: 17277342). (SP) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant was reported as pathogenic in PMID: 35789182, citing LOVD as the source. However, the variant is not currently listed in LOVD and therefore, there is uncertainty regarding this classification. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Correction: Consensus statement on standards and guidelines for the molecular diagnostics of Alport syndrome: refining the ACMG criteria. | Savige J | European journal of human genetics : EJHG | 2024 | PMID: 36721056 |
| Pathogenicity of missense variants affecting the collagen IV α5 carboxy non-collagenous domain in X-linked Alport syndrome. | Gibson JT | Scientific reports | 2022 | PMID: 35789182 |
| Identification of 47 novel mutations in patients with Alport syndrome and thin basement membrane nephropathy. | Weber S | Pediatric nephrology (Berlin, Germany) | 2016 | PMID: 26809805 |
| 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 |
| 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 |
| A novel Cys1638Tyr NC1 domain substitution in alpha5(IV) collagen causes Alport syndrome with late onset renal failure without hearing loss or eye abnormalities. | Wilson JC | Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association | 2007 | PMID: 17277342 |
| 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 |
Text-mined citations for this variant ...
HelpRecord last updated Jul 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.