NM_033380.3(COL4A5):c.1690G>T (p.Gly564Cys) AND X-linked Alport syndrome

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Dec 29, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000021315.6

Allele description [Variation Report for NM_033380.3(COL4A5):c.1690G>T (p.Gly564Cys)]

NM_033380.3(COL4A5):c.1690G>T (p.Gly564Cys)

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.1690G>T (p.Gly564Cys)

HGVS:

NC_000023.11:g.108597479G>T
NG_011977.2:g.162556G>T
NM_000495.5:c.1690G>T
NM_033380.3:c.1690G>TMANE SELECT
NP_000486.1:p.Gly564Cys
NP_203699.1:p.Gly564Cys
LRG_232t1:c.1690G>T
LRG_232t2:c.1690G>T
LRG_232:g.162556G>T
LRG_232p1:p.Gly564Cys
LRG_232p2:p.Gly564Cys
NC_000023.10:g.107840709G>T
NG_011977.1:g.162556G>T
NM_000495.4:c.1690G>T

Protein change:

G564C

Links:

dbSNP: rs281874674

NCBI 1000 Genomes Browser:

rs281874674

Molecular consequence:

NM_000495.5:c.1690G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_033380.3:c.1690G>T - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001427202	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 27, 2019)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002819893	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Dec 29, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 32939031, 19019929, 19965530, 29270492 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001427202

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 27, 2019)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002819893

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Dec 29, 2022)

germline

clinical testing

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

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Clinical impact of genomic testing in patients with suspected monogenic kidney disease.

Jayasinghe K, Stark Z, Kerr PG, Gaff C, Martyn M, Whitlam J, Creighton B, Donaldson E, Hunter M, Jarmolowicz A, Johnstone L, Krzesinski E, Lunke S, Lynch E, Nicholls K, Patel C, Prawer Y, Ryan J, See EJ, Talbot A, Trainer A, Tytherleigh R, et al.

Genet Med. 2021 Jan;23(1):183-191. doi: 10.1038/s41436-020-00963-4. Epub 2020 Sep 17.

PubMed [citation]

PMID:: 32939031
PMCID:: PMC7790755

See all PubMed Citations (5)

Details of each submission

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV001427202.2

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

Description

A heterozygous missense variant, NM_000495.4(COL4A5):c.1690G>T, has been identified in exon 24 of 51 of the COL4A5 gene. The variant is predicted to result in a major amino acid change from glycine to cysteine at position 564 of the protein (NP_000486.1(COL4A5):p.(Gly564Cys)). The glycine residue at this position has very high conservation (100 vertebrates, UCSC), and is located within the collagen triple helix repeat region. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is absent in the gnomAD population database. The variant has been previously described as pathogenic in two patients with alport retinopathy (ClinVar, Colville, D., et al. (2009)). A different variant in the same codon resulting in a change to arginine has also been reported as likely pathogenic in a clinical testing setting (ClinVar). Subsequent analysis of parental samples indicated this variant was due to a de novo event. Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002819893.1

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

Description

Variant summary: COL4A5 c.1690G>T (p.Gly564Cys) results in a non-conservative amino acid change to a highly conserved residue in the encoded protein sequence. A different missense variant affecting this residue has been classified as likely pathogenic in ClinVar (c.1690G>C, p.Gly564Arg), and other missense variants near this amino acid have been found in association with Alport syndrome (HGMD). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183307 control chromosomes. c.1690G>T has been reported in the literature in individuals affected with Alport Syndrome 1, including at least one individual with de novo occurrence (Colville_2009, Yamamyra_2017, Jayasinghe_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One submitter has provided a clinical-significance assessment for this variant to ClinVar after 2014, and it as pathogenic. The variant changes a highly conserved glycine residue within the triple-helical region. Alterations of glycine residues within the collagen triple-helix are common mechanisms of disease. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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

Last Updated: Feb 20, 2024

ClinVar

Relating variation to medicine