NM_033380.3(COL4A5):c.2917+1G>C AND X-linked Alport syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Dec 23, 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:: RCV000021453.5

Allele description [Variation Report for NM_033380.3(COL4A5):c.2917+1G>C]

NM_033380.3(COL4A5):c.2917+1G>C

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.2917+1G>C

HGVS:

NC_000023.11:g.108622826G>C
NG_011977.2:g.187903G>C
NM_000495.5:c.2917+1G>C
NM_033380.3:c.2917+1G>CMANE SELECT
LRG_232t1:c.2917+1G>C
LRG_232t2:c.2917+1G>C
LRG_232:g.187903G>C
NC_000023.10:g.107866056G>C
NM_000495.4:c.2917+1G>C
NM_033380.2:c.2917+1G>C

Links:

dbSNP: rs104886371

NCBI 1000 Genomes Browser:

rs104886371

Molecular consequence:

NM_000495.5:c.2917+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_033380.3:c.2917+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]

Functional consequence:

exon loss [Variation Ontology: 0381]

Condition(s)

Name:: X-linked Alport syndrome (ATS1)
Synonyms:: NEPHROPATHY AND DEAFNESS, X-LINKED; Alport syndrome 1, X-linked recessive; Alport Syndrome and Thin Basement Membrane Nephropathy
Identifiers:: MONDO: MONDO:0010520; MedGen: C4746986; Orphanet: 63; Orphanet: 88917; OMIM: 301050

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001190327	Institute of Clinical Laboratory Science, Nanjing University Affiliated Jinling Hospital	no assertion criteria provided	Pathogenic (May 21, 2017)	not applicable	in vitro
SCV002819763	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Dec 23, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 30586318, 8940267, 32659759 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001190327

Institute of Clinical Laboratory Science, Nanjing University Affiliated Jinling Hospital

no assertion criteria provided

Pathogenic
(May 21, 2017)

not applicable

in vitro

SCV002819763

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Dec 23, 2022)

germline

clinical testing

PubMed (3)
[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	not applicable	not applicable	not provided	not provided	not provided	not provided	not provided	in vitro

Citations

PubMed

Diagnostic Utility of Exome Sequencing for Kidney Disease.

Groopman EE, Marasa M, Cameron-Christie S, Petrovski S, Aggarwal VS, Milo-Rasouly H, Li Y, Zhang J, Nestor J, Krithivasan P, Lam WY, Mitrotti A, Piva S, Kil BH, Chatterjee D, Reingold R, Bradbury D, DiVecchia M, Snyder H, Mu X, Mehl K, Balderes O, et al.

N Engl J Med. 2019 Jan 10;380(2):142-151. doi: 10.1056/NEJMoa1806891. Epub 2018 Dec 26.

PubMed [citation]

PMID:: 30586318
PMCID:: PMC6510541

Spectrum of mutations in the COL4A5 collagen gene in X-linked Alport syndrome.

Knebelmann B, Breillat C, Forestier L, Arrondel C, Jacassier D, Giatras I, Drouot L, Deschênes G, Grünfeld JP, Broyer M, Gubler MC, Antignac C.

Am J Hum Genet. 1996 Dec;59(6):1221-32.

PubMed [citation]

PMID:: 8940267
PMCID:: PMC1914854

See all PubMed Citations (3)

Details of each submission

From Institute of Clinical Laboratory Science, Nanjing University Affiliated Jinling Hospital, SCV001190327.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	in vitro	not provided

Description

A heterozygous variant c.2767g > t (p.gly923cys) was found in exon 32 of COL4A5 gene in the proband, which is a new variant. Sanger sequencing confirmed that the mutation was co isolated from the disease in the family. In vitro minigene experiment showed that the mutation of c.2767g > t could cause 96 bases missing in exon 33 of COL4A5 gene

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	not applicable	not applicable	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, SCV002819763.1

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

Description

Variant summary: COL4A5 c.2917+1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Lv_2020). The variant was absent in 180606 control chromosomes. c.2917+1G>C has been reported in the literature as a hemizygous genotype in two patients affected with Alport Syndrome 1, X-Linked Recessive (Knebelman_1996, Groopman_2019) and as a heterozygous genotype in 2 females (proband and mother) with Hematuria, a related phenotype (Lv_2020). These data indicate that the variant is likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments to ClinVar after 2014 and classified 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: Sep 29, 2024

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