ClinVar Miner

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

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Total submissions: 5
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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 2018-05-15 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.
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

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