NM_000091.5(COL4A3):c.3210+1G>A AND Autosomal recessive Alport syndrome

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Apr 19, 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:: RCV000670389.3

Allele description [Variation Report for NM_000091.5(COL4A3):c.3210+1G>A]

NM_000091.5(COL4A3):c.3210+1G>A

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.3210+1G>A

HGVS:

NC_000002.12:g.227290887G>A
NG_011591.1:g.131323G>A
NM_000091.5:c.3210+1G>AMANE SELECT
LRG_230t1:c.3210+1G>A
LRG_230:g.131323G>A
NC_000002.11:g.228155603G>A
NM_000091.4:c.3210+1G>A

Links:

dbSNP: rs1553762314

NCBI 1000 Genomes Browser:

rs1553762314

Molecular consequence:

NM_000091.5:c.3210+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

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
SCV000795234	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Nov 7, 2017)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001623348	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Apr 19, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000795234

Counsyl

criteria provided, single submitter

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

Likely pathogenic
(Nov 7, 2017)

unknown

clinical testing

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

Citation Link,

SCV001623348

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Apr 19, 2021)

germline

clinical testing

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

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

COL4A3/COL4A4 mutations and features in individuals with autosomal recessive Alport syndrome.

Storey H, Savige J, Sivakumar V, Abbs S, Flinter FA.

J Am Soc Nephrol. 2013 Dec;24(12):1945-54. doi: 10.1681/ASN.2012100985. Epub 2013 Sep 19.

PubMed [citation]

PMID:: 24052634
PMCID:: PMC3839543

Details of each submission

From Counsyl, SCV000795234.1

#	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, SCV001623348.1

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

Description

Variant summary: COL4A3 c.3210+1G>A 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: Two predict that the variant abolishes a 5-prime splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 244902 control chromosomes. c.3210+1G>A has been reported in the literature in at least one individual affected with Alport Syndrome, Autosomal Recessive (e.g. Storey_2013). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories cited the variant as likely pathogenic. Based on the evidence outlined above, the variant was 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: Oct 8, 2024

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