NM_033380.3(COL4A5):c.2500G>C (p.Gly834Arg) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Oct 22, 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:: RCV000991628.18

Allele description [Variation Report for NM_033380.3(COL4A5):c.2500G>C (p.Gly834Arg)]

NM_033380.3(COL4A5):c.2500G>C (p.Gly834Arg)

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.2500G>C (p.Gly834Arg)

HGVS:

NC_000023.11:g.108615015G>C
NG_011977.2:g.180092G>C
NM_000495.5:c.2500G>C
NM_033380.3:c.2500G>CMANE SELECT
NP_000486.1:p.Gly834Arg
NP_203699.1:p.Gly834Arg
LRG_232t1:c.2500G>C
LRG_232t2:c.2500G>C
LRG_232:g.180092G>C
LRG_232p1:p.Gly834Arg
LRG_232p2:p.Gly834Arg
NC_000023.10:g.107858245G>C
NG_011977.1:g.180092G>C
NM_033380.1:c.2500G>C

Protein change:

G834R

Links:

dbSNP: rs281874696

NCBI 1000 Genomes Browser:

rs281874696

Molecular consequence:

NM_000495.5:c.2500G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_033380.3:c.2500G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001143249	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (May 16, 2019)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 20378821, 26467025
SCV001587739	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 22, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 20378821, 7695699, 8218237, 19344236, 23720012, 27627812, 28492532
SCV001805384	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Nov 15, 2019)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001143249

Athena Diagnostics

criteria provided, single submitter

(Athena Diagnostics Criteria)

Pathogenic
(May 16, 2019)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV001587739

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 22, 2023)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV001805384

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Nov 15, 2019)

germline

clinical testing

Citation Link

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

A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

Karbassi I, Maston GA, Love A, DiVincenzo C, Braastad CD, Elzinga CD, Bright AR, Previte D, Zhang K, Rowland CM, McCarthy M, Lapierre JL, Dubois F, Medeiros KA, Batish SD, Jones J, Liaquat K, Hoffman CA, Jaremko M, Wang Z, Sun W, Buller-Burckle A, et al.

Hum Mutat. 2016 Jan;37(1):127-34. doi: 10.1002/humu.22918. Epub 2015 Oct 29.

PubMed [citation]

PMID:: 26467025
PMCID:: PMC4737317

Genotype-phenotype correlation in X-linked Alport syndrome.

Bekheirnia MR, Reed B, Gregory MC, McFann K, Shamshirsaz AA, Masoumi A, Schrier RW.

J Am Soc Nephrol. 2010 May;21(5):876-83. doi: 10.1681/ASN.2009070784. Epub 2010 Apr 8.

PubMed [citation]

PMID:: 20378821
PMCID:: PMC2865738

See all PubMed Citations (8)

Details of each submission

From Athena Diagnostics, SCV001143249.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The variant disrupts a glycine residue in the canonical Gly-X-Y repeats of the triple helix domain, which are required for stability and structure of this protein. Therefore it is expected to severely affect the function of the protein. Found in at least one symptomatic patient, and not found in general population data. Predicted to have a damaging effect on the protein. One other pathogenic or likely pathogenic variant affects the same amino acid.

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001587739.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 834 of the COL4A5 protein (p.Gly834Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Alport syndrome (PMID: 20378821; Invitae). ClinVar contains an entry for this variant (Variation ID: 24529). 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. 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). For these reasons, this variant has been classified as 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

From GeneDx, SCV001805384.1

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

Description

Affects a glycine residue in a Gly-X-Y motif in the triple helical region of the COL4A5 gene, where the majority of pathogenic missense variants occur, and is predicted to disrupt normal protein folding and function (Stenson et al., 2014; Jais et al., 2000); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 20378821)

#	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: Nov 24, 2024

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