NM_000091.5(COL4A3):c.2954G>T (p.Gly985Val) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Sep 21, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000485138.4

Allele description [Variation Report for NM_000091.5(COL4A3):c.2954G>T (p.Gly985Val)]

NM_000091.5(COL4A3):c.2954G>T (p.Gly985Val)

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.2954G>T (p.Gly985Val)

HGVS:

NC_000002.12:g.227289222G>T
NG_011591.1:g.129658G>T
NM_000091.5:c.2954G>TMANE SELECT
NP_000082.2:p.Gly985Val
NP_000082.2:p.Gly985Val
LRG_230t1:c.2954G>T
LRG_230:g.129658G>T
LRG_230p1:p.Gly985Val
NC_000002.11:g.228153938G>T
NM_000091.4:c.2954G>T
Q01955:p.Gly985Val

Protein change:

G985V; GLY985VAL

Links:

UniProtKB: Q01955#VAR_030948; OMIM: 120070.0008; dbSNP: rs121912827

NCBI 1000 Genomes Browser:

rs121912827

Molecular consequence:

NM_000091.5:c.2954G>T - 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
SCV000568798	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Apr 19, 2023)	germline	clinical testing	Citation Link,
SCV004294024	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Sep 21, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 11961012, 25307543, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000568798

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Apr 19, 2023)

germline

clinical testing

Citation Link,

SCV004294024

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Sep 21, 2023)

germline

clinical testing

PubMed (3)
[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

Mutations in theCOL4A4 and COL4A3 genes cause familial benign hematuria.

Badenas C, Praga M, Tazón B, Heidet L, Arrondel C, Armengol A, Andrés A, Morales E, Camacho JA, Lens X, Dávila S, Milà M, Antignac C, Darnell A, Torra R.

J Am Soc Nephrol. 2002 May;13(5):1248-1254. doi: 10.1681/ASN.V1351248.

PubMed [citation]

PMID:: 11961012

Collagen type IV-related nephropathies in Portugal: pathogenic COL4A3 and COL4A4 mutations and clinical characterization of 25 families.

Nabais Sá MJ, Storey H, Flinter F, Nagel M, Sampaio S, Castro R, Araújo JA, Gaspar MA, Soares C, Oliveira A, Henriques AC, da Costa AG, Abreu CP, Ponce P, Alves R, Pinho L, Silva SE, de Moura CP, Mendonça L, Carvalho F, Pestana M, Alves S, et al.

Clin Genet. 2015 Nov;88(5):456-61. doi: 10.1111/cge.12521. Epub 2014 Nov 10.

PubMed [citation]

PMID:: 25307543

See all PubMed Citations (3)

Details of each submission

From GeneDx, SCV000568798.5

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

Description

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Affects a glycine residue in a Gly-X-Y motif in the triple helical region of the COL4A3 gene; This variant is associated with the following publications: (PMID: 11961012, 33838161)

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV004294024.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 985 of the COL4A3 protein (p.Gly985Val). This variant is present in population databases (rs121912827, gnomAD 0.01%). This missense change has been observed in individuals with Clinical features of Alport syndrome (PMID: 11961012, 25307543). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17490). 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 COL4A3 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been 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: Sep 29, 2024

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