NM_000091.5(COL4A3):c.272G>A (p.Gly91Asp) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Dec 19, 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:: RCV001366917.4

Allele description [Variation Report for NM_000091.5(COL4A3):c.272G>A (p.Gly91Asp)]

NM_000091.5(COL4A3):c.272G>A (p.Gly91Asp)

Genes:

MFF-DT:MFF divergent transcript [Gene - HGNC]
COL4A3:collagen type IV alpha 3 chain [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q36.3

Genomic location:

Preferred name:

NM_000091.5(COL4A3):c.272G>A (p.Gly91Asp)

HGVS:

NC_000002.12:g.227244357G>A
NG_011591.1:g.84793G>A
NM_000091.5:c.272G>AMANE SELECT
NP_000082.2:p.Gly91Asp
LRG_230:g.84793G>A
NC_000002.11:g.228109073G>A

Protein change:

G91D

Links:

dbSNP: rs1414411811

NCBI 1000 Genomes Browser:

rs1414411811

Molecular consequence:

NM_000091.5:c.272G>A - 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
SCV001563241	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 19, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30295827, 28492532
SCV003933596	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Dec 14, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001563241

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 19, 2023)

germline

clinical testing

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

SCV003933596

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Dec 14, 2022)

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Panel sequencing distinguishes monogenic forms of nephritis from nephrosis in children.

Schapiro D, Daga A, Lawson JA, Majmundar AJ, Lovric S, Tan W, Warejko JK, Fessi I, Rao J, Airik M, Gee HY, Schneider R, Widmeier E, Hermle T, Ashraf S, Jobst-Schwan T, van der Ven AT, Nakayama M, Shril S, Braun DA, Hildebrandt F.

Nephrol Dial Transplant. 2019 Mar 1;34(3):474-485. doi: 10.1093/ndt/gfy050.

PubMed [citation]

PMID:: 30295827
PMCID:: PMC6399484

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV001563241.3

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

Description

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 91 of the COL4A3 protein (p.Gly91Asp). This variant is present in population databases (no rsID available, gnomAD 0.06%). This missense change has been observed in individual(s) with proteinuria and hematuria (PMID: 30295827; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1057850). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on COL4A3 protein function. This variant disrupts the p.Gly91 amino acid residue in COL4A3. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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, SCV003933596.1

#	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 COL4A3 gene, where the majority of pathogenic missense variants occur, and is predicted to disrupt normal protein folding and function (HGMD, Jais et al., 2000); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30295827, 10752524)

#	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: Feb 28, 2024

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