chr2-227280529-ACTCCCTGGACTTCCAGGT-A

Position:

• chr2-227280529-ACTCCCTGGACTTCCAGGT-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PM4 PP5_Very_Strong

The NM_000091.5(COL4A3):​c.2323_2340delCTTCCAGGTCTCCCTGGA​(p.Leu775_Gly780del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.00000205 in 1,461,808 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: COL4A3 NM_000091.5 conservative_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 6.50

Genes affected

COL4A3 (HGNC:2204): (collagen type IV alpha 3 chain) Type IV collagen, the major structural component of basement membranes, is a multimeric protein composed of 3 alpha subunits. These subunits are encoded by 6 different genes, alpha 1 through alpha 6, each of which can form a triple helix structure with 2 other subunits to form type IV collagen. This gene encodes alpha 3. In the Goodpasture syndrome, autoantibodies bind to the collagen molecules in the basement membranes of alveoli and glomeruli. The epitopes that elicit these autoantibodies are localized largely to the non-collagenous C-terminal domain of the protein. A specific kinase phosphorylates amino acids in this same C-terminal region and the expression of this kinase is upregulated during pathogenesis. This gene is also linked to an autosomal recessive form of Alport syndrome. The mutations contributing to this syndrome are also located within the exons that encode this C-terminal region. Like the other members of the type IV collagen gene family, this gene is organized in a head-to-head conformation with another type IV collagen gene so that each gene pair shares a common promoter. [provided by RefSeq, Jun 2010]

MFF-DT (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000091.5.
• PP5: Variant 2-227280529-ACTCCCTGGACTTCCAGGT-A is Pathogenic according to our data. Variant chr2-227280529-ACTCCCTGGACTTCCAGGT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 556542.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227280529-ACTCCCTGGACTTCCAGGT-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A3	NM_000091.5	c.2323_2340delCTTCCAGGTCTCCCTGGA	p.Leu775_Gly780del	conservative_inframe_deletion	30/52	ENST00000396578.8	NP_000082.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A3	ENST00000396578.8	c.2323_2340delCTTCCAGGTCTCCCTGGA	p.Leu775_Gly780del	conservative_inframe_deletion	30/52	1	NM_000091.5	ENSP00000379823.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461808 Hom.: 0 AF XY: 0.00000275 AC XY: 2 AN XY: 727200

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive Alport syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Feb 06, 2018

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 22, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the COL4A3 protein in which other variant(s) (p.Gly777Asp) have been determined to be pathogenic (PMID: 26633401, 27904025). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 556542). This variant has been observed in individual(s) with Alport syndrome (PMID: 24052634, 24854265, 28780565). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This variant, c.2323_2340del, results in the deletion of 6 amino acid(s) of the COL4A3 protein (p.Leu775_Gly780del), but otherwise preserves the integrity of the reading frame. -

Autosomal dominant Alport syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Jun 24, 2022

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with COL4A3-related nephropathy. Glycine changes that are part of a G-X-Y repeat in the triple helix of a collagen domain are known to have a dominant negative effect (PMID: 12028435). (I) 0108 - This gene is associated with both recessive (Alport syndrome 2 MIM#203780) and dominant disease (Alport syndrome 3 MIM#104200 and benign familial hematuria MIM#141200) (OMIM). (I) 0213 - In-frame deletion in a non-repetitive region that has high conservation. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0601 - Variant is located in the well-established triple helix repeat domain (Decipher). (SP) 0704 - Another inframe deletion variant comparable to the one identified in this case has limited previous evidence for pathogenicity. A variant that results in the deletion of one set of G-X-Y repeat within this region (p.Leu778_Gly780del) has been reported as likely pathogenic (ClinVar). (SP) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported in both heterozygote and compound heterozygote states in multiple individuals with Alport syndrome with conflicting classifications from VUS to pathogenic (ClinVar, LOVD, PMID: 24052634, 24854265, 28780565, 33226606). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed) (by segregation analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Benign familial hematuria;C4746745:Autosomal recessive Alport syndrome;C5882663:Autosomal dominant Alport syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 25, 2022

- -

Hematuria Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Sydney Genome Diagnostics, Children's Hospital Westmead

Aug 28, 2018

This patient is heterozygous for the c.2323_2340del (p.Leu775_Gly780del) variant in exon 30 of the COL4A3 gene. This variant results in an inframe deletion of six amino acid residues (Leu-Pro-Gly-Leu-Pro-Gly) in the triple helical domain of the alpha 3 chain of type IV collagen. To our knowledge, this nucleotide variant has not been previously reported. However, a variant involving an inframe deletion of the same six amino acids, c.2313_2330del (p.Leu775_Gly780del), has been previously reported in trans with another pathogenic COL4A3 variant in a patient with autosomal recessive Alport syndrome in the literature (Storey et al 2013 J Am Soc Nephrol 24:1945-1954). This variant is likely to be pathogenic as an inframe deletion of six amino acids is likely to disrupt the folding of the triple helix domain. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1306992119; hg19: chr2-228145245;