Submissions for variant NM_181486.4(TBX5):c.1135A>T (p.Met379Leu)

dbSNP: rs759607221

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001114220	SCV001272072	uncertain significance	Holt-Oram syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003532878	SCV004301251	uncertain significance	Aortic valve disease 2	2022-12-19	criteria provided, single submitter	clinical testing	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. 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 TBX5 protein function. ClinVar contains an entry for this variant (Variation ID: 883628). This variant has not been reported in the literature in individuals affected with TBX5-related conditions. This variant is present in population databases (rs759607221, gnomAD 0.0009%). This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 379 of the TBX5 protein (p.Met379Leu).
Ambry Genetics	RCV004678961	SCV005168714	uncertain significance	Cardiovascular phenotype	2024-05-11	criteria provided, single submitter	clinical testing	The p.M379L variant (also known as c.1135A>T), located in coding exon 8 of the TBX5 gene, results from an A to T substitution at nucleotide position 1135. The methionine at codon 379 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.