Submissions for variant NM_172351.3(CD46):c.286+2T>G

gnomAD frequency: 0.00004  dbSNP: rs769742294

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000600566	SCV000713264	likely pathogenic	Atypical hemolytic-uremic syndrome	2017-07-28	criteria provided, single submitter	clinical testing	The c.286+2T>G (NM_002389.4 c.286+2T>G) variant in CD46 has been previously repo rted in at least 4 heterozygous, 1 compound heterozygous, and 3 homozygous indiv iduals with atypical hemolytic uremic syndrome, and segregated with disease in o ne homozygous sibling (Fremeaux-Bacci 2006, Saunders 2007, Maga 2010, Bresin 201 3, Alberti 2013, Brocklebank 2014, Bhatia 2015, Phillips 2016, Sheerin 2016, and Besbas 2017, and Bhatia 2015). This variant occurs in the invariant region (+/ - 1,2) of the splice consensus sequence and has been demonstrated to impact spli cing (Fremeaux-Bacci 2006). It has been identified in 0.01% (11/111554) of Europ ean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomAD.broadi nstitute.org; dbSNP rs769742294). Available data suggests that this variant is i nherited in an autosomal dominant manner with incomplete penetrance, and milder phenotype in heterozygotes and more severe, earlier-onset presentation in homozy gotes. In summary, the c.286+2T>C variant is likely pathogenic for atypical hem olytic uremic syndrome based upon observations in affected individuals and predi cted impact on the protein, though it may show reduced penetrance.
Johns Hopkins Genomics, Johns Hopkins University	RCV001250520	SCV001425316	pathogenic	Atypical hemolytic-uremic syndrome with MCP/CD46 anomaly	2020-04-27	criteria provided, single submitter	clinical testing	This CD46 variant (rs769742294) is rare (<0.1%) in a large population dataset (gnomAD: 13/249756 total alleles; 0.005205%; no homozygotes). It has been previously reported in individuals with aHUS with incomplete penetrance. This variant destroys a canonical splice donor site and is predicted to affect normal exon 2 splicing. A single submitter in ClinVar classifies this variant as likely pathogenic. We consider it to be pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV001843953	SCV002103194	pathogenic	not provided	2021-10-06	criteria provided, single submitter	clinical testing	PP1, PM3, PS4, PVS1
Institute of Human Genetics, University of Leipzig Medical Center	RCV001250520	SCV002526719	pathogenic	Atypical hemolytic-uremic syndrome with MCP/CD46 anomaly	2022-05-27	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PVS1, PM3_STR, PS4_SUP identified in patient with polygenic aHUS together with variant in CFH (ClinVar-ID: 1068249)
Fulgent Genetics, Fulgent Genetics	RCV001250520	SCV002811014	pathogenic	Atypical hemolytic-uremic syndrome with MCP/CD46 anomaly	2022-05-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001843953	SCV004363907	pathogenic	not provided	2024-01-12	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 2 of the CD46 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CD46 are known to be pathogenic (PMID: 16621965, 23431077). This variant is present in population databases (rs769742294, gnomAD 0.01%). Disruption of this splice site has been observed in individual(s) with hemolytic uremic syndrome (PMID: 16762990, 23431077, 26307634, 26559391). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 505831). Studies have shown that disruption of this splice site alters CD46 gene expression (PMID: 24944786, 26559391). 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	RCV003994042	SCV004813919	pathogenic	Familial Atypical Hemolytic-Uremic Syndrome	2024-02-07	criteria provided, single submitter	clinical testing	Variant summary: CD46 c.286+2T>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing, resulting in the deletion of 144 bp in exon 2 (Fremeaux-Bacchi_2006). The variant allele was found at a frequency of 5.2e-05 in 249756 control chromosomes (gnomAD). c.286+2T>G has been reported in the literature in multiple individuals affected with Genetic Atypical Hemolytic Uremic Syndrome, both in the homozygous state and in heterozygous individuals with incomplete penetrance (Fremeaux-Bacchi_2006, Khandelwal_CD46_CKJ_2018). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 16762990, 29644059). ClinVar contains an entry for this variant (Variation ID: 505831). Based on the evidence outlined above, the variant was classified as pathogenic.
Sydney Genome Diagnostics, Children's Hospital Westmead	RCV000600566	SCV001449450	pathogenic	Atypical hemolytic-uremic syndrome	2018-10-24	no assertion criteria provided	clinical testing	This patient is heterozygous for a known pathogenic variant, c.286+2T>G, in the CD46 gene. In silico analysis (using Alamut visual v2.6) predicts this variant to abolish the consensus splice donor site at c.286, resulting in the skipping of exon 2. This variant in the heterozygote form has been reported in a patient with end-stage renal disease (ESRD) who developed atypical haemolytic uremic syndrome (aHUS) following renal transplantation from her asymptomatic mother who was also heterozygote for the variant (Alberti et al 2013 Am J Transplant 13:2201-2206). This variant, in both heterozygote and homozygote form, has been reported in patients who developed aHUS after a trigger, such as S. flexneri diarrhoeal illness or dengue shock syndrome (Brocklebank et al 2014 Clin Kidney J 7:286-288; Bhatia et al 2015 Pediatr Nephrol Aug 26). However, the latter paper also reported this variant, in both heterozygote and homozygote form, in asymptomatic individuals who were 50 to 100% deficient of CD46.