Submissions for variant NM_000092.5(COL4A4):c.489+1G>A

gnomAD frequency: 0.00001  dbSNP: rs1040287646

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000681912	SCV001575285	pathogenic	not provided	2023-11-21	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 7 of the COL4A4 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in COL4A4 are known to be pathogenic (PMID: 21196518, 24854265, 25307543). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with clinical features of Alport syndrome (PMID: 28632965; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 562437). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002499208	SCV002808189	likely pathogenic	Autosomal recessive Alport syndrome; Benign familial hematuria	2022-04-27	criteria provided, single submitter	clinical testing
Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center	RCV002512124	SCV002822966	pathogenic	Autosomal recessive Alport syndrome	2019-09-27	criteria provided, single submitter	clinical testing	The c.489+1G>A variant in the COL4A4 gene is a canonical splice site variant, which affects a donor splice site in intron 7 (47 introns total; NM_000092.4). A substitution at this site could produce a protein with modified function or cause the protein not to be expressed. While it is unknown which effect on the protein this variant will cause, loss-of-function variants distal to this variant have been reported to be associated with disease. 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. A different splice variant at the same position, c.489+1G>C, has been reported in a heterozygous state in one family with three individuals (one parent and two offspring) with microscopic hematuria, and later onset Alport-related nephropathy progressing to end-stage renal disease, suggestive of autosomal dominant inheritance (PMID: 28632965). Based on the evidence presented, this variant is classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004527737	SCV004104170	pathogenic	COL4A4-related disorder	2023-05-19	criteria provided, single submitter	clinical testing	The COL4A4 c.489+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in heterozygous state in an individual with glomerulopathy (Table S7, patient CKD292, Groopman et al. 2019. PubMed ID: 30586318). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Variants that disrupt the consensus splice donor site in COL4A4 are expected to be pathogenic. This variant is interpreted as pathogenic.
Gharavi Laboratory, Columbia University	RCV000681912	SCV000809395	likely pathogenic	not provided	2018-09-16	no assertion criteria provided	research
Natera, Inc.	RCV001829889	SCV002084173	likely pathogenic	Alport syndrome	2020-03-16	no assertion criteria provided	clinical testing