ClinVar Miner

Submissions for variant NM_000091.5(COL4A3):c.4441C>T (p.Arg1481Ter)

gnomAD frequency: 0.00003  dbSNP: rs121912824
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000019036 SCV000790786 pathogenic Autosomal recessive Alport syndrome 2017-04-26 criteria provided, single submitter clinical testing
GeneDx RCV000760446 SCV000890330 pathogenic not provided 2018-11-21 criteria provided, single submitter clinical testing The R1481X nonsense variant in the COL4A3 gene has been reported previously in association with autosomal recessive Alport syndrome (Mochizuki et al., 1994; Lemmink et al., 1994). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The variant is observed in 1/15018 (0.0067%) alleles from individuals of European background in large population cohorts (Lek et al., 2016). We consider this variant to be pathogenic.
Fulgent Genetics, Fulgent Genetics RCV000763473 SCV000894255 pathogenic Autosomal dominant Alport syndrome; Autosomal recessive Alport syndrome; Benign familial hematuria 2021-10-19 criteria provided, single submitter clinical testing
Invitae RCV000760446 SCV001380340 pathogenic not provided 2024-01-16 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg1481*) in the COL4A3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL4A3 are known to be pathogenic (PMID: 8956999, 24854265, 26809805, 27281700). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with Alport syndrome (PMID: 9195222, 29854973). ClinVar contains an entry for this variant (Variation ID: 17484). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000019036 SCV002074433 pathogenic Autosomal recessive Alport syndrome 2022-01-26 criteria provided, single submitter clinical testing Variant summary: COL4A3 c.4441C>T (p.Arg1481X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 249352 control chromosomes. c.4441C>T has been reported in the literature in individuals affected with Alport Syndrome, Autosomal Recessive (ie. Mochizuki_1994, Vega_2003). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000019036 SCV000039323 pathogenic Autosomal recessive Alport syndrome 1997-01-01 no assertion criteria provided literature only
Natera, Inc. RCV001273243 SCV001456040 pathogenic Alport syndrome 2020-09-16 no assertion criteria provided clinical testing

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