Submissions for variant NM_033380.3(COL4A5):c.2965_2982del (p.Asp989_Gly994del)

dbSNP: rs104886374

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Gharavi Laboratory, Columbia University	RCV000681846	SCV000809323	likely pathogenic	not provided	2018-09-16	criteria provided, single submitter	research
Invitae	RCV000681846	SCV001407268	pathogenic	not provided	2021-10-10	criteria provided, single submitter	clinical testing	This variant disrupts the triple helix domain of COL4A5. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). In COL4A5, missense variants at these glycine residues are significantly enriched in individuals with disease (PMID: 23720012, 27627812) compared to the general population (ExAC). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 24580). This variant is also known as 3161-3178del del987-992. This variant has been observed in individuals with clinical features of Alport syndrome (PMID: 10094548; Invitae). This variant is not present in population databases (ExAC no frequency). This variant, c.2965_2982del, results in the deletion of 6 amino acid(s) of the COL4A5 protein (p.Asp989_Gly994del), but otherwise preserves the integrity of the reading frame.
Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center	RCV002512053	SCV002822968	likely pathogenic	X-linked Alport syndrome	2019-10-10	criteria provided, single submitter	clinical testing	The p.Asp989_Gly994del variant in the COL4A5 gene is a hemizygous in-frame deletion variant, which results in the removal of six amino acids in coding exon 34 of the COL4A5 gene (51 coding exons in total; NP_000486.1) and maps to the triple-helical region of the protein. This variant has not been observed in the Genome Aggregation Database (gnomAD), indicating it is not a common benign variant in the populations represented in this database. This variant has been reported in in a hemizygous male with end stage renal failure, characteristic basement membrane changes and a positive family history (PMID: 10094548). In ClinVar, this in-frame deletion overlaps with multiple Pathogenic/ Likely Pathogenic variants. Based on the evidence presented, this variant is classified as Likely Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000681846	SCV004702310	pathogenic	not provided	2024-01-01	criteria provided, single submitter	clinical testing	COL4A5: PM1:Strong, PM2, PM4, PS4:Moderate, PP4