ClinVar Miner

Submissions for variant NM_172351.3(CD46):c.565T>G (p.Tyr189Asp)

gnomAD frequency: 0.00002  dbSNP: rs202071781
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002537716 SCV003524028 uncertain significance not provided 2024-05-22 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 189 of the CD46 protein (p.Tyr189Asp). This variant is present in population databases (rs202071781, gnomAD 0.005%). This missense change has been observed in individual(s) with atypical hemolytic uremic syndrome (aHUS), however some individuals also carried variants in other aHUS-causing genes (PMID: 16762990, 20059470, 20513133, 21810760, 23314101, 24029428, 29644059, 33213850, 34169201). This variant is also known as Y155D in the MCP gene. ClinVar contains an entry for this variant (Variation ID: 988106). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CD46 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CD46 function (PMID: 16762990). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV004596435 SCV005090900 uncertain significance not specified 2024-07-31 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV005012707 SCV005643397 uncertain significance Atypical hemolytic-uremic syndrome with MCP/CD46 anomaly 2024-01-05 criteria provided, single submitter clinical testing
Sydney Genome Diagnostics, Children's Hospital Westmead RCV001328049 SCV001449209 likely pathogenic Atypical hemolytic-uremic syndrome 2018-05-30 no assertion criteria provided clinical testing This patient is heterozygous for a variant in CD46, c.565T>G, which is predicted to cause an amino acid substitution p.Tyr189Asp. This variant has been previously reported either as a single heterozygous variant or in conjunction with other CD46 variants, in aHUS patients (Fremeaux-Bacchi et al. 2006. J Am Soc Nephrol 17:2017-2025; Bu et al. 2014. J Am Soc Nephrol 25: 55-64). Patients with the c.565T>G variants had decreased levels of the protein product MCP, and the function of p.Tyr189Asp mutant MCP was also shown to be decreased in vitro (Fremeaux-Bacchi et al. 2006). c.565T>G has been reported in the ExAC database (http://exac.broadinstitute.org) with a very low allele frequency (1/121036 alleles). This variant is considered to be a likely pathogenic according to the ACMG guidelines.

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