NM_033380.3(COL4A5):c.2605G>A (p.Gly869Arg) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Aug 17, 2023
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:: RCV000311568.7

Allele description

NM_033380.3(COL4A5):c.2605G>A (p.Gly869Arg)

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.2605G>A (p.Gly869Arg)

Other names:

p.G869R

HGVS:

NC_000023.11:g.108620354G>A
NG_011977.2:g.185431G>A
NM_000495.5:c.2605G>A
NM_033380.3:c.2605G>AMANE SELECT
NP_000486.1:p.Gly869Arg
NP_203699.1:p.Gly869Arg
LRG_232t1:c.2605G>A
LRG_232t2:c.2605G>A
LRG_232:g.185431G>A
LRG_232p1:p.Gly869Arg
LRG_232p2:p.Gly869Arg
NC_000023.10:g.107863584G>A
NG_011977.1:g.185431G>A
NM_000495.4:c.2605G>A
NM_000495.5:c.2605G>A
NM_033380.1:c.2605G>A
NM_033380.2:c.2605G>A
P29400:p.Gly869Arg
p.(Gly869Arg)

Protein change:

G869R

Links:

UniProtKB: P29400#VAR_001953; dbSNP: rs104886189

NCBI 1000 Genomes Browser:

rs104886189

Molecular consequence:

NM_000495.5:c.2605G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_033380.3:c.2605G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Neosilurus gloveri isolate NGDalh.1 cytochrome b gene, partial cds; mitochondrial
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000329767	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Pathogenic (Sep 2, 2016)	germline	clinical testing	Citation Link,
SCV001214001	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 17, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 7695699, 8218237, 19344236, 23720012, 27627812, 7599631, 30577881, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000329767

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Pathogenic
(Sep 2, 2016)

germline

clinical testing

Citation Link,

SCV001214001

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 17, 2023)

germline

clinical testing

PubMed (8)
[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
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Crystal and molecular structure of a collagen-like peptide at 1.9 A resolution.

Bella J, Eaton M, Brodsky B, Berman HM.

Science. 1994 Oct 7;266(5182):75-81.

PubMed [citation]

PMID:: 7695699

Characterization of collagen-like peptides containing interruptions in the repeating Gly-X-Y sequence.

Long CG, Braswell E, Zhu D, Apigo J, Baum J, Brodsky B.

Biochemistry. 1993 Nov 2;32(43):11688-95.

PubMed [citation]

PMID:: 8218237

See all PubMed Citations (8)

Details of each submission

From GeneDx, SCV000329767.6

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

Description

The G869R pathogenic variant in the COL4A5 gene has been reported previously in multiple unrelated individuals with X-linked Alport syndrome (Boye et al., 1995; Knebelman et al., 1996; Plant et al., 1999). The G869R variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G869R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret G869R as a pathogenic variant.

#	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

From Invitae, SCV001214001.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the triple helix domain of COL4A5. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). In COL4A5, missense variants at these glycine residues are significantly enriched in individuals with disease (PMID: 23720012, 27627812) compared to the general population (ExAC). 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: 24543). This variant is also known as c.2808G>A. This missense change has been observed in individuals with Alport syndrome (PMID: 7599631, 30577881). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 869 of the COL4A5 protein (p.Gly869Arg).

#	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: Jul 23, 2024

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