NM_000091.5(COL4A3):c.2621_2622delinsT (p.Gly874fs) AND Autosomal recessive Alport syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Apr 21, 2021
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:: RCV000667128.4

Allele description [Variation Report for NM_000091.5(COL4A3):c.2621_2622delinsT (p.Gly874fs)]

NM_000091.5(COL4A3):c.2621_2622delinsT (p.Gly874fs)

Genes:

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

Variant type:

Indel

Cytogenetic location:

2q36.3

Genomic location:

Preferred name:

NM_000091.5(COL4A3):c.2621_2622delinsT (p.Gly874fs)

HGVS:

NC_000002.12:g.227282497_227282498delinsT
NG_011591.1:g.122933_122934delinsT
NM_000091.5:c.2621_2622delinsTMANE SELECT
NP_000082.2:p.Gly874fs
LRG_230:g.122933_122934delinsT
NC_000002.11:g.228147213_228147214delinsT
NM_000091.4:c.2621_2622delGAinsT
NM_000091.5:c.2621_2622delinsT

Protein change:

G874fs

Links:

dbSNP: rs1553760257

NCBI 1000 Genomes Browser:

rs1553760257

Molecular consequence:

NM_000091.5:c.2621_2622delinsT - frameshift variant - [Sequence Ontology: SO:0001589]

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000791529	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Pathogenic (May 17, 2017)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000917261	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Apr 21, 2021)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 25514610, 11134255, 24052634, 28117080, 24854265 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000791529

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))

Pathogenic
(May 17, 2017)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV000917261

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Apr 21, 2021)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical 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 (5)

Details of each submission

From Counsyl, SCV000791529.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000917261.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Variant summary: COL4A3 c.2621_2622delinsT (p.Gly874ValfsX9) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 3.6e-05 in 280726 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in COL4A3 causing Alport Syndrome, Autosomal Recessive (3.6e-05 vs 0.0019), allowing no conclusion about variant significance. c.2621_2622delinsT has been reported in the literature in multiple individuals affected with Alport Syndrome, Autosomal Recessive, including one homozygous patient (Heidet_2001, Storey_2013, Moriniere_2014, Papazachariou_2014, Bierzynska_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was 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

Last Updated: Mar 16, 2024

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