Submissions for variant NM_172351.3(CD46):c.944-1G>C

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002625517	SCV002955085	likely pathogenic	not provided	2022-05-25	criteria provided, single submitter	clinical testing	Disruption of this splice site has been observed in individual(s) with hemolytic uremic syndrome (Invitae). This variant is present in population databases (rs140298514, gnomAD 0.03%). This sequence change affects an acceptor splice site in intron 9 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site.
Johns Hopkins Genomics, Johns Hopkins University	RCV003150838	SCV003839123	likely pathogenic	Atypical hemolytic-uremic syndrome with MCP/CD46 anomaly	2023-02-27	criteria provided, single submitter	clinical testing	This CD46 canonical splice variant (rs140298514) is rare (<0.1%) in a large population dataset (gnomAD v3.1.2: 12/151114 total alleles; 0.008%; no homozygotes). It has been reported in ClinVar (Variation ID 1917135), but has not been reported in the literature, to our knowledge. This variant destroys a canonical splice acceptor site and is predicted to cause abnormal gene splicing. We consider c.989-1G>C in CD46 to be likely pathogenic.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003150838	SCV003919785	uncertain significance	Atypical hemolytic-uremic syndrome with MCP/CD46 anomaly	2023-01-18	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature but is present in the Genome Aggregation Database (Highest reported MAF 0.02% [10/41120]; https://gnomad.broadinstitute.org/variant/1-207783291-G-C?dataset=gnomad_r3). Evolutionary conservation and computational prediction tools for this variant are limited or unavailable. Of note, this variant alters the consensus splice sequence (+/- 1,2), which is predicted to result in an absent or abnormal protein. However, based on nucleotide position, this variant may result in an in-frame deletion. Further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.