Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001997331 | SCV002232802 | uncertain significance | not provided | 2023-09-14 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 340 of the CFI protein (p.Ile340Thr). This variant is present in population databases (rs769419740, gnomAD 0.04%). This missense change has been observed in individual(s) with CFI-related conditions (PMID: 17106690, 20106822, 22410797, 24142231, 27268256, 31440263, 32098865). This variant is also known as Ile322Thr. ClinVar contains an entry for this variant (Variation ID: 1449003). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CFI protein function. Experimental studies have shown that this missense change affects CFI function (PMID: 17597211, 35069568, 36643920). 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003492712 | SCV004241361 | likely pathogenic | Factor I deficiency | 2023-12-20 | criteria provided, single submitter | clinical testing | Variant summary: CFI c.1019T>C (p.Ile340Thr) results in a non-conservative amino acid change located in the Serine proteases, trypsin domain (IPR001254) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 1613494 control chromosomes (i.e., 171 alleles, no homozygotes; gnomAD v4). This frequency is not significantly higher than estimated for a pathogenic variant in CFI causing Complement Factor I Deficiency (0.00011 vs 0.0011), allowing no conclusion about variant significance. c.1019T>C has been reported in the literature in at least two compound heterozygous individuals affected with Complement Factor I Deficiency (e.g., Haerynck_2013, Altmann_2020) as well as heterozygous individuals affected with atypical hemolytic uremic syndrome (e.g., Geelen_2007, LeQuintrec_2008, Westra_2010, Geerdink_2012, Seddon_2013, Gleeson_2016, Sissy_2019) and age-related macular degeneration (e.g., Geerlings_2018). These data indicate that the variant is likely to be associated with autosomal recessive disease and may also be associated with autosomal dominant disease, although potentially with reduced penetrance given the number of heterozygotes in the gnomAD control population. Several publications report experimental evidence evaluating an impact on protein function, consistently finding that the variant results in <10% of normal cofactor activity (e.g., Kavanagh_2008, Gerogianni_2023, deJong_2021). The following publications have been ascertained in the context of this evaluation (PMID: 17106690, 18557729, 17597211, 20106822, 22410797, 24036952, 24142231, 27268256, 31440263, 29888403, 37954579, 32098865, 32510551, 35069568). One submitter has reported clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. |