ClinVar Miner

Submissions for variant NM_000091.5(COL4A3):c.40_63del (p.Leu14_Leu21del) (rs876657397)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000172875 SCV000919245 pathogenic Alport syndrome, autosomal recessive 2019-06-06 criteria provided, single submitter clinical testing Variant summary: COL4A3 c.40_63del24 (p.Leu14_Leu21del) results in an in-frame deletion that is predicted to remove eight amino acids from the COL4A3 signal peptide sequence of the encoded protein. The variant allele was found at a frequency of 0.00022 in 125078 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in COL4A3 causing autosomal recessive Alport Syndrome (0.00022 vs 0.002), allowing no conclusion about variant significance. c.40_63del24 has been reported in the literature in multiple individuals affected with autosomal recessive Alport Syndrome worldwide (Zhang_2012, Oka_2014, Webb_2014, Chiereghin_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a disruption of COL4A3 signal peptide, possibly altering protein secretion (Chiereghin_2017). No other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000807286 SCV000947331 pathogenic not provided 2020-10-19 criteria provided, single submitter clinical testing This variant, c.40_63del, results in the deletion of 8 amino acids of the COL4A3 protein (p.Leu14_Leu21del), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed to segregate with Alport syndrome in a single family, and has been identified in additional unrelated individuals affected with Alport syndrome (PMID: 23927549, 28570636). ClinVar contains an entry for this variant (Variation ID: 192299). This variant has been reported to disrupt protein function in vitro (PMID: 28570636). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV001535917 SCV001752565 pathogenic Alport syndrome 3, autosomal dominant; Alport syndrome, autosomal recessive; Benign familial hematuria 2021-06-30 criteria provided, single submitter clinical testing
GeneDx RCV000807286 SCV001815037 pathogenic not provided 2021-04-20 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect on protein localization; variant results in diffuse localization in the cytoplasm and nucleus (Chiereghin et al., 2017); In-frame deletion of 8 amino acids in a non-repeat region; Published with a carrier frequency within the Ashkenazi Jewish population of 1 in 183, and may be a founder variant in this population (Webb et al., 2014); This variant is associated with the following publications: (PMID: 29801666, 24633401, 28570636, 23927549, 22887978, 14582039, 12028435)
OMIM RCV000172875 SCV000223865 pathogenic Alport syndrome, autosomal recessive 2014-08-01 no assertion criteria provided literature only
Natera, Inc. RCV001272220 SCV001453992 pathogenic Alport syndrome 2020-09-16 no assertion criteria provided clinical testing

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