NM_033380.3(COL4A5):c.4581C>G (p.Cys1527Trp) AND X-linked Alport syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Nov 5, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV003994650.1

Allele description [Variation Report for NM_033380.3(COL4A5):c.4581C>G (p.Cys1527Trp)]

NM_033380.3(COL4A5):c.4581C>G (p.Cys1527Trp)

Gene:

COL4A5:collagen type IV alpha 5 chain [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq22.3

Genomic location:

Preferred name:

NM_033380.3(COL4A5):c.4581C>G (p.Cys1527Trp)

HGVS:

NC_000023.11:g.108692800C>G
NG_011977.2:g.257877C>G
NM_000495.5:c.4563C>G
NM_033380.3:c.4581C>GMANE SELECT
NP_000486.1:p.Cys1521Trp
NP_203699.1:p.Cys1527Trp
LRG_232t1:c.4563C>G
LRG_232t2:c.4581C>G
LRG_232:g.257877C>G
LRG_232p1:p.Cys1521Trp
LRG_232p2:p.Cys1527Trp
NC_000023.10:g.107936030C>G

Protein change:

C1521W

Molecular consequence:

NM_000495.5:c.4563C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_033380.3:c.4581C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: X-linked Alport syndrome (ATS1)
Synonyms:: NEPHROPATHY AND DEAFNESS, X-LINKED; Alport syndrome 1, X-linked recessive; Alport Syndrome and Thin Basement Membrane Nephropathy
Identifiers:: MONDO: MONDO:0010520; MedGen: C4746986; Orphanet: 63; Orphanet: 88917; OMIM: 301050

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peroxiredoxin 3, isoform CRA_b [Homo sapiens]
peroxiredoxin 3, isoform CRA_b [Homo sapiens]
gi|119569782|gb|EAW49397.1||gnl|WGS |hCP1781754

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004812425	Molecular Genetics, Royal Melbourne Hospital See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 5, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 9535854, 35243249, 35789182, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004812425

Molecular Genetics, Royal Melbourne Hospital

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Nov 5, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Glomerular basement membrane. Identification of a novel disulfide-cross-linked network of alpha3, alpha4, and alpha5 chains of type IV collagen and its implications for the pathogenesis of Alport syndrome.

Gunwar S, Ballester F, Noelken ME, Sado Y, Ninomiya Y, Hudson BG.

J Biol Chem. 1998 Apr 10;273(15):8767-75.

PubMed [citation]

PMID:: 9535854

NanoLuc reporters identify COL4A5 nonsense mutations susceptible to drug-induced stop codon readthrough.

Omachi K, Kai H, Roberge M, Miner JH.

iScience. 2022 Mar 18;25(3):103891. doi: 10.1016/j.isci.2022.103891.

PubMed [citation]

PMID:: 35243249
PMCID:: PMC8866893

See all PubMed Citations (4)

Details of each submission

From Molecular Genetics, Royal Melbourne Hospital, SCV004812425.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change in COL4A5 is predicted to replace cysteine with tryptophan at codon 1527, p.(Cys1527Trp). The cysteine residue is highly conserved (100 vertebrates, UCSC), and is a critical residue involved in a disulphide bond in the NC1 domain (PMID: 9535854). There is a large physicochemical difference between cysteine and tryptophan. This variant is absent from the population database gnomAD v2.1 and v3.1. To our knowledge, this variant has not been reported in any individuals with COL4A5-related disease in the relevant scientific literature. The variant alters COL4 trimer formation in an in vitro assay in HEK293 cells (PMID: 35243249). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.904). Another missense variant c.4561T>A, p.Cys1527Ser in the same codon (with a similar physicochemical difference) has been classified as likely pathogenic (PMID: 35789182). Based on the classification scheme RMH Modified ACMG Guidelines v1.6.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM1, PM5, PM2_Supporting, PS3_Supporting, PP3.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 20, 2024

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