ClinVar Miner

Submissions for variant NM_080647.1(TBX1):c.1399_1428del (p.Ala467_Ala476del) (rs746335599)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000620329 SCV000735530 uncertain significance Cardiovascular phenotype 2016-10-21 criteria provided, single submitter clinical testing The c.1399_1428del30 variant (also known as p.A467_A476del) is located in coding exon 8 of the TBX1 gene. This variant results from an in-frame deletion of 30 nucleotides at positions 1399 to 1428. This results in the deletion of 10 alanine residues at codons 467 to 476 in a tract of 15 alanines. This variant has not been reported in the literature to date; however, a similar deletion, c.1404_1412del9, occurring within the same polyalanine tract in TBX1 has been described in a patient with DiGeorge syndrome/velocardiofacial syndrome and in the patient's mother, although clinical details were limited. Additionally, other deletions within the same region of polyalanines in TBX1 were detected in two control subjects. In the same study, aside from deletions within this polyalanine tract in TBX1, a different patient with interruption of the aortic arch was reported to have an expansion caused by an in-frame duplication, c.1399-1428dup30 (Gong W et al. J Med Genet. 2001;38(12):E45). This duplication was later reported in another patient with isolated left pulmonary artery, absent pulmonary vein, scoliosis, and abnormal facial characteristics, in which the authors discussed almost complete loss of transcriptional activity due to cytoplasmatic aggregation of the mutant protein as a result of this duplication (Rauch R et al. J Med Genet. 2010;47(5):321-31). Based on the available evidence to date, it is suggested that disruption of the polyalanine tract length in TBX1 may affect cellular function; however, additional studies are needed to further predict the functional impact of the c.1399_1428del30 variant. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 2603 samples (5206 alleles) with coverage at this position. These amino acid positions are well conserved on limited sequence alignment in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV001215829 SCV001387592 uncertain significance DiGeorge Syndrome 2019-05-09 criteria provided, single submitter clinical testing This variant, c.1399_1428del, results in the deletion of 10 amino acid(s) of the TBX1 protein (p.Ala467_Ala476del), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with TBX1-related conditions. ClinVar contains an entry for this variant (Variation ID: 518565). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the affected amino acid(s) is currently unknown. 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.

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