ClinVar Miner

Submissions for variant NM_000091.4(COL4A3):c.4421T>C (p.Leu1474Pro) (rs200302125)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000521759 SCV000617789 uncertain significance not specified 2017-10-13 criteria provided, single submitter clinical testing The L1474P variant has been reported previously in association with COL4A3-related disorders (Chatterjee et al., 2013; Nabais et al., 2015; Gast et al., 2015). However, it has also been referred to as a polymorphism (Longo et al., 2002; Wang et al., 2004). The variant is observed in 620/126548 (0.4899%) alleles from individuals of European background in the ExAC dataset (Lek et al., 2016). L1474P is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Athena Diagnostics Inc RCV000710822 SCV000841127 uncertain significance not provided 2020-01-17 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000710822 SCV000854987 uncertain significance not provided 2018-07-27 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000778597 SCV000914905 likely pathogenic COL4A3-Related Disorders 2018-12-17 criteria provided, single submitter clinical testing The COL4A3 c.4421T>C (p.Leu1474Pro) variant has been reported in at least five studies and is found in a total of nine probands, including five probands with clinical symptoms of Alport syndrome, two of which are siblings, in a compound heterozygous state and four proband in a heterozygous state, including one sibling pair (Chatterjee et al. 2013; Nabais Sa et al. 2015; Gast et al. 2016; Bierzynska et al. 2017; Brandt et al. 2018). This included two compound heterozygous probands with end stage renal disease (Nabais Sa et al. 2015). The remaining three compound heterozygous probands were identified to have variants in additional genes known to be associated with glomerulopathy (Chatterjee et al. 2013; Gast et al. 2016). The c.4421T>C (p.Leu1474Pro) variant was also observed in a presumed heterozygous state in the unaffected brother of a compound heterozygote and this brother's son (Chatterjee et al. 2013). Control data are unavailable for this variant, which is reported at a frequency of 0.004899 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the evidence, the p.Leu1474Pro variant is classified as likely pathogenic for COL4A3-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000710822 SCV001113607 likely benign not provided 2020-12-06 criteria provided, single submitter clinical testing
Mendelics RCV000987047 SCV001136235 uncertain significance Alport syndrome, autosomal recessive 2019-05-28 criteria provided, single submitter clinical testing
Institute of Human Genetics, Klinikum rechts der Isar RCV000987047 SCV001149720 likely pathogenic Alport syndrome, autosomal recessive 2020-04-20 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000710822 SCV001153345 uncertain significance not provided 2020-03-01 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000521759 SCV001365646 benign not specified 2020-01-15 criteria provided, single submitter clinical testing The p.Leu1474Pro variant in COL4A3 is classified as benign because it has been identified in 0.5% (627/128566) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1.
Victorian Clinical Genetics Services,Murdoch Childrens Research Institute RCV000987047 SCV001427144 uncertain significance Alport syndrome, autosomal recessive 2019-03-27 criteria provided, single submitter clinical testing A heterozygous missense variant was identified, NM_000091.4(COL4A3):c.4421T>C in exon 48 of 52 of the COL4A3 gene. This substitution is predicted to create a moderate amino acid change from leucine to proline at position 1474 of the protein, NP_000082.2(COL4A3):p.(Leu1474Pro). The leucine at this position has very high conservation (100 vertebrates, UCSC), and is located within the C4 functional domain. In silico software predicts this variant to be pathogenic (PolyPhen, SIFT, CADD, MutationTaster). The variant is present in the gnomAD population database at a frequency of 0.27% (748 heterozygotes; 0 homozygotes). Previous reports of the pathogenicity of this variant are conflicting (ClinVar, Ottlewski, I. et al. (2019), Schapiro, D. et al. (2019)). Based on information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS). NB: This variant has been reclassified to a VARIANT of UNCERTAIN SIGNIFICANCE (VUS) due to the reanalysis of published literature.
Institute of Human Genetics, University of Leipzig Medical Center RCV000735744 SCV001428971 pathogenic Alport syndrome 3, autosomal dominant 2017-08-11 criteria provided, single submitter clinical testing
Department of Otolaryngology – Head & Neck Surgery,Cochlear Implant Center RCV001375164 SCV001571722 likely pathogenic Hearing impairment 2021-04-12 criteria provided, single submitter clinical testing PS1_Strong, PM1_Moderate, PM2_Moderate, PP3_Supporting
Bioscientia Institut fuer Medizinische Diagnostik GmbH,Sonic Healthcare RCV000735744 SCV000863899 uncertain significance Alport syndrome 3, autosomal dominant 2018-06-14 no assertion criteria provided clinical testing
Natera, Inc. RCV001276575 SCV001462974 benign Alport syndrome 2020-01-12 no assertion criteria provided clinical testing

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