ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs1040287646
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Total submissions: 6
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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 (, 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

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