Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
ARUP Laboratories, |
RCV001001112 | SCV001158249 | uncertain significance | Agammaglobulinemia 8, autosomal dominant | 2019-03-11 | criteria provided, single submitter | clinical testing | The p.Ala8Val variant (rs376780559) has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the Genome Aggregation Database (gnomAD) with an overall population frequency of 0.01 percent in the European Non-Finnish (identified on 11 out of 91,746 chromosomes). The alanine at position 8 is moderately conserved and computational analyses of the effects of the p.Ala8Val variant on protein structure and function is deleterious (SIFT: damaging, PolyPhen-2: possibly damaging). Altogether, there is not enough evidence to classify the p.Ala8Val variant with certainty. |
Invitae | RCV001869426 | SCV002295409 | uncertain significance | not provided | 2023-10-05 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 8 of the TCF3 protein (p.Ala8Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with TCF3-related conditions. ClinVar contains an entry for this variant (Variation ID: 811326). 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) performed at Invitae indicates that this missense variant is expected to disrupt TCF3 protein function. 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. |
Prevention |
RCV003928657 | SCV004746422 | uncertain significance | TCF3-related condition | 2024-02-27 | criteria provided, single submitter | clinical testing | The TCF3 c.23C>T variant is predicted to result in the amino acid substitution p.Ala8Val. This variant was reported in the heterozygous state in an individual with E47 transcription factor deficiency (Taskin et al. 2023. PubMed ID: 38154455). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |