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NM_000091.5(COL4A3):c.4001G>A (p.Gly1334Glu) AND Autosomal recessive Alport syndrome

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jun 20, 2022
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV002271709.3

Allele description [Variation Report for NM_000091.5(COL4A3):c.4001G>A (p.Gly1334Glu)]

NM_000091.5(COL4A3):c.4001G>A (p.Gly1334Glu)

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.4001G>A (p.Gly1334Glu)
HGVS:
  • NC_000002.12:g.227303904G>A
  • NG_011591.1:g.144340G>A
  • NM_000091.5:c.4001G>AMANE SELECT
  • NP_000082.2:p.Gly1334Glu
  • LRG_230t1:c.4001G>A
  • LRG_230:g.144340G>A
  • NC_000002.11:g.228168620G>A
  • NM_000091.4:c.4001G>A
Protein change:
G1334E
Links:
dbSNP: rs375290088
NCBI 1000 Genomes Browser:
rs375290088
Molecular consequence:
  • NM_000091.5:c.4001G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Autosomal recessive Alport syndrome (ATS2)
Synonyms:
Alport syndrome recessive type; Nephropathy and deafness; ALPORT SYNDROME 2, AUTOSOMAL RECESSIVE; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0008762; MedGen: C4746745; Orphanet: 63; Orphanet: 88919; OMIM: 203780

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002555997Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Pathogenic
(Jun 20, 2022) 		germlineclinical testing

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

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Frequency of COL4A3/COL4A4 mutations amongst families segregating glomerular microscopic hematuria and evidence for activation of the unfolded protein response. Focal and segmental glomerulosclerosis is a frequent development during ageing.

Papazachariou L, Demosthenous P, Pieri M, Papagregoriou G, Savva I, Stavrou C, Zavros M, Athanasiou Y, Ioannou K, Patsias C, Panagides A, Potamitis C, Demetriou K, Prikis M, Hadjigavriel M, Kkolou M, Loukaidou P, Pastelli A, Michael A, Lazarou A, Arsali M, Damianou L, et al.

PLoS One. 2014;9(12):e115015. doi: 10.1371/journal.pone.0115015.

PubMed [citation]
PMID:
25514610
PMCID:
PMC4267773

Structure of the human type IV collagen gene COL4A3 and mutations in autosomal Alport syndrome.

Heidet L, Arrondel C, Forestier L, Cohen-Solal L, Mollet G, Gutierrez B, Stavrou C, Gubler MC, Antignac C.

J Am Soc Nephrol. 2001 Jan;12(1):97-106. doi: 10.1681/ASN.V12197.

PubMed [citation]
PMID:
11134255
See all PubMed Citations (4)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002555997.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

Variant summary: COL4A3 c.4001G>A (p.Gly1334Glu) results in a non-conservative amino acid change located in the Collagen triple helix repeat (IPR008160) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 249558 control chromosomes (gnomAD and publication data). c.4001G>A has been reported in the literature in multiple individuals affected with Alport Syndrome or familial microscopic hematuria due to thin basement membrane nephropathy, and this variant segregated with the disease (Heidet_2001, Papazachariou_2014, Stefanou_2015). These data indicate that the variant is very likely to be associated with disease. Functional studies report this variant showed retention of mutant collagens and differential activation of the unfolded protein response cascade (Pieri_2014, Papazachariou_2014). One ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Apr 15, 2024