Submissions for variant NM_001379200.1(TBX1):c.823G>A (p.Glu275Lys)

dbSNP: rs144848597

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001202887	SCV001374021	uncertain significance	DiGeorge syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 266 of the TBX1 protein (p.Glu266Lys). This variant is present in population databases (rs144848597, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with TBX1-related conditions. ClinVar contains an entry for this variant (Variation ID: 934486). 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 not expected to disrupt TBX1 protein function with a negative predictive value of 80%. 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.
GeneDx	RCV001570784	SCV001795134	likely benign	not provided	2020-11-16	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV002069302	SCV002495982	uncertain significance	Conotruncal heart malformations; Velocardiofacial syndrome; DiGeorge syndrome; Tetralogy of Fallot	2021-06-18	criteria provided, single submitter	clinical testing	TBX1 NM_080647.1 exon 6 p.Glu266Lys (c.796G>A): This variant has not been reported in the literature but is present in 0.06% (10/15288) of Latino alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/22-19765069-G-A?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:934486). Evolutionary conservation suggests that this variant may impact the protein; computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.