Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000913108 | SCV001058246 | likely benign | not provided | 2024-12-30 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003489966 | SCV004241229 | likely benign | not specified | 2023-12-18 | criteria provided, single submitter | clinical testing | Variant summary: C3 c.4369G>C (p.Asp1457His) results in a non-conservative amino acid change located in the alpha-macroglobulin, receptor-binding domain (IPR009048) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 1609596 control chromosomes, predominantly at a frequency of 0.0033 within the African or African-American subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3-fold of the estimated maximal expected allele frequency for a pathogenic variant in C3 causing C3 Deficiency phenotype (0.0011), suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.4369G>C has not, to our knowledge, been reported in individuals affected with C3 Deficiency, but has been reported in the literature in the heterozygous state in individuals affected with and/or with clinical features of Familial Atypical Hemolytic-Uremic Syndrome, however, at least two of these individuals were of African ancestry and these publications did not provide strong evidence for causality (e.g. Szarvas_2016, Vaught_2018, Fremeaux-Bacchi_2019). These reports do not provide unequivocal conclusions about association of the variant with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30674459, 26826462, 29563339). One submitter has cited a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. |
| Mayo Clinic Laboratories, |
RCV000913108 | SCV005408675 | uncertain significance | not provided | 2024-08-27 | criteria provided, single submitter | clinical testing | BP4 |