Submissions for variant NM_181486.4(TBX5):c.902C>G (p.Ser301Cys)

gnomAD frequency: 0.00001  dbSNP: rs973621936

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000805691	SCV000945657	uncertain significance	Aortic valve disease 2	2022-06-04	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 301 of the TBX5 protein (p.Ser301Cys). This variant has not been reported in the literature in individuals affected with TBX5-related conditions. ClinVar contains an entry for this variant (Variation ID: 650528). 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. 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.
Genetics and Molecular Pathology, SA Pathology	RCV002272364	SCV002556822	uncertain significance	Holt-Oram syndrome	2022-06-23	criteria provided, single submitter	clinical testing	The TBX5 c.902C>G variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE (PM2, PP3) This variant is a single nucleotide change in exon 8/9 of the TBX5 gene, which is predicted to change the amino acid serine at position 301 in the protein to cysteine. The variant is in dbSNP (rs973621936) but is rare in population databases (gnomAD 3/152063, 0 homozygote) (PM2). The variant has been reported in ClinVar as VUS (Variation ID: 650528). The variant has not been reported in HGMD. Computational predictions support a deleterious effect on the gene or gene product (PP3).
Ambry Genetics	RCV002370142	SCV002686332	uncertain significance	Cardiovascular phenotype	2021-09-21	criteria provided, single submitter	clinical testing	The p.S301C variant (also known as c.902C>G), located in coding exon 7 of the TBX5 gene, results from a C to G substitution at nucleotide position 902. The serine at codon 301 is replaced by cysteine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002272364	SCV002768028	uncertain significance	Holt-Oram syndrome	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0103 - Dominant negative and loss of function and gain of function are known mechanisms of disease in this gene and are associated with Holt-Oram syndrome (MIM#142900). Both loss of function and gain of function are known mechanisms of disease for this gene, and have both been demonstrated by missense variants (PMID: 18451335). Dominant negative has also been suggested as a mechanism in patients with severe congenital heart disease (PMID: 30552424). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 30552424). (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (3 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (3 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated transactivation domain (PMID: 15355425). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. An alternative change to a isoleucine in a different transcript has been reported in a patient with Holt-Oram syndrome with non-classical features (PMID: 11183182, 15096952). The same variant has also been reported in another patient with heart and limb defects (PMID: 15355425). (SP) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported once as a variant of uncertain significance (ClinVar). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV002272364	SCV002814577	uncertain significance	Holt-Oram syndrome	2021-08-23	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV002272364	SCV003827075	uncertain significance	Holt-Oram syndrome	2021-10-19	criteria provided, single submitter	clinical testing