Submissions for variant NM_000092.5(COL4A4):c.2638del (p.Ala880fs)

dbSNP: rs778043831

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000665226	SCV000789309	pathogenic	Autosomal recessive Alport syndrome	2017-01-27	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001245708	SCV001419011	pathogenic	not provided	2024-06-03	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ala880Hisfs*70) in the COL4A4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL4A4 are known to be pathogenic (PMID: 21196518, 24854265, 25307543). This variant is present in population databases (rs778043831, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with Alport syndrome (PMID: 12325029, 17216251, 24052634). This variant is also known as 2864delG. ClinVar contains an entry for this variant (Variation ID: 550471). For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004788084	SCV001427145	pathogenic	Hematuria, benign familial, 1	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function is a known mechanism of disease for this gene and is associated with Alport syndrome 2 (MIM#203780 and thin basement membrane nephropathy (MIM#141200). Dominant negative is a suspected mechanism of disease for this gene as it is a structural protein (PMIDs: 12028435, 24046192). (I) 0108 - This gene is associated with both recessive and dominant disease. Alport syndrome typically has biallelic inheritance, although rare cases of monoallelic inheritance have been reported (PMID: 28704582). Thin basement membrane nephropathy (TBMN) and focal segmental glomerulosclerosis (FSGS) are associated with autosomal dominant inheritance (OMIM, PMIDs: 16467446, 17942953). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 (3 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar, and has been observed in individuals with recessive and dominant Alport syndrome (PMIDs: 24052634, 36239278, 17216251). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV001580287	SCV001809957	pathogenic	Glomerulonephritis	2021-01-08	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005004322	SCV002775581	pathogenic	Autosomal recessive Alport syndrome; Hematuria, benign familial, 1	2024-05-30	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV001829830	SCV004812606	pathogenic	Alport syndrome	2023-04-11	criteria provided, single submitter	clinical testing	This sequence change in COL4A4 is a frameshift variant predicted to cause a premature stop codon, p.(Ala880Hisfs*70), in biologically relevant exon 31/48 leading to nonsense-mediated decay in a gene in which loss of function is an established disease mechanism (PMID: 20301386). The highest population minor allele frequency in the population database gnomAD v2.1 is 0.01% (2/15,438 alleles) in the African/African American population. This variant has been detected in at least two unrelated individuals with Alport syndrome. Of those individuals, one individual was homozygous and one compound heterozygous for the variant and a pathogenic variant was confirmed in trans by family testing (PMID: 24052634). The variant has been reported to segregate with haematuria in heterozygous individuals from at least two families (PMID: 12325029, 30506145). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM3, PP1.
Mayo Clinic Laboratories, Mayo Clinic	RCV001245708	SCV005413558	pathogenic	not provided	2024-02-15	criteria provided, single submitter	clinical testing	PM3_strong, PS4_moderate, PVS1
Natera, Inc.	RCV001829830	SCV002078890	pathogenic	Alport syndrome	2020-08-31	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004544926	SCV004787545	pathogenic	COL4A4-related disorder	2023-12-28	no assertion criteria provided	clinical testing	The COL4A4 c.2638delG variant is predicted to result in a frameshift and premature protein termination (p.Ala880Hisfs*70). This variant has been reported to be pathogenic for autosomal recessive Alport syndrome and autosomal dominant thin glomerular basement membrane disease (TBMD) (see for example, Dagher et al. 2002. PubMed ID: 12325029; Jayasinghe et al. 2020. PubMed ID: 32939031, Suppl. Table S2). This variant is reported in 0.013% of alleles in individuals of African descent in gnomAD. Frameshift variants in COL4A4 are expected to be pathogenic. This variant is interpreted as pathogenic.