Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001853399 | SCV002169003 | pathogenic | not provided | 2023-07-17 | criteria provided, single submitter | clinical testing | Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. Experimental studies have shown that this missense change affects TCF3 function (PMID: 24216514). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 225870). This missense change has been observed in individual(s) with agammaglobulinemia (PMID: 24216514). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 555 of the TCF3 protein (p.Glu555Lys). The TCF3 gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_001136139.3, and corresponds to NM_003200.4:c.1823-508G>A in the primary transcript. For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV002515606 | SCV003560427 | pathogenic | Inborn genetic diseases | 2021-09-09 | criteria provided, single submitter | clinical testing | The c.1663G>A (p.E555K) alteration is located in exon 17 (coding exon 17) of the TCF3 gene. This alteration results from a G to A substitution at nucleotide position 1663, causing the glutamic acid (E) at amino acid position 555 to be replaced by a lysine (K). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration was reported de novo in multiple patients with agammaglobulinemia (Boisson, 2013; Al Sheikh, 2021). This amino acid position is highly conserved in available vertebrate species. In vitro functional expression studies and studies of patient cells with the E555K mutant showed that while the E47 transcription factor protein does localize properly to the nucleus, but it did not perform proper DNA binding and acted in a dominant-negative manner when co-expressed with wildtype. The authors concluded that E47 plays a critical role in enforcing the block in development of B cell precursors that lack functional antigen receptors (Boisson, 2013). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000211091 | SCV004020919 | pathogenic | Agammaglobulinemia 8, autosomal dominant | 2023-06-29 | criteria provided, single submitter | clinical testing | Variant summary: TCF3 NM_003200.3:c.1823-508G>A, also annotated as NM_001136139.3:c.1663G>A (p.E555K), is located at a position not widely known to affect splicing within one of the alternate transcripts of TCF3. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. As a missense variant in an alternate transcript, TCF3 c.1663G>A (p.Glu555Lys) results in a conservative amino acid change located in the Myc-type, basic helix-loop-helix (bHLH) domain (IPR011598) of the encoded protein sequence. Four of five in-silico tools predict a damaging impact on protein function. The variant was absent in 248552 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. This variant has been reported in the literature as the missense change p.E555K from the alternate transcript encoding the E47 isoform. This variant was reported in five unrelated heterozygous individuals affected with Agammaglobulinaemia and failure of B-cell development (Boisson_2013, Al_Sheikh_2021), and parental testing suggested this was a de novo mutation in all of the patients. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function for the p.E555K missense change in cells that were transfected with a vector to produce the mutated E47 protein. This demonstrated that the mutant E47 localizes to the nucleus normally but shows substantially reduced binding to the E5 immunoglobulin enhancer probe in vitro compared to the wildtype protein, and exerts a strong dominant negative effect when binding to the probe as a homodimer with wildtype E47 (Boisson_2013). The following publications have been ascertained in the context of this evaluation (PMID: 24216514, 33905048). Three submitters have cited clinical-significance assessments for the variant (in the context of the E47 isoform p.E555K missense change) to ClinVar after 2014, and classified it as pathogenic. Based on the evidence outlined above demonstrating an impact of this nucleotide change to the E47 isoform of TCF3, the variant was classified as pathogenic. |
| OMIM | RCV000211091 | SCV000268057 | pathogenic | Agammaglobulinemia 8, autosomal dominant | 2022-04-12 | no assertion criteria provided | literature only |