Submissions for variant NM_003239.5(TGFB3):c.1080G>A (p.Thr360=)

dbSNP: rs1555360212

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002544825	SCV000816374	uncertain significance	Rienhoff syndrome	2023-07-13	criteria provided, single submitter	clinical testing	This sequence change affects codon 360 of the TGFB3 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the TGFB3 protein. This variant also falls at the last nucleotide of exon 6, which is part of the consensus splice site for this exon. 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 568400). This variant has not been reported in the literature in individuals affected with TGFB3-related conditions. This variant is not present in population databases (gnomAD no frequency).
GeneDx	RCV001766474	SCV001988632	likely pathogenic	not provided	2022-02-21	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); Alters the last nucleotide of the exon and is predicted to destroy the splice donor site and result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798959	SCV002043222	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2022-03-28	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV001766474	SCV005874199	uncertain significance	not provided	2024-11-25	criteria provided, single submitter	clinical testing	PM2, PP3
Molecular Genetics, Royal Melbourne Hospital	RCV005250091	SCV005900497	uncertain significance	Hereditary disorder of connective tissue	2024-11-04	criteria provided, single submitter	clinical testing	This sequence change is a synonymous (silent) variant in the last nucleotide of exon 6 of TGFB3. The results from an in silico splicing predictor (SpliceAI) indicate that this variant may impact splicing by disrupting the donor splice site of intron 6 of TGFB3. RNA assays have not been conducted to confirm this prediction. This variant is absent from the population database gnomAD v4.1.0. This variant has conflicting reports in ClinVar (ClinVar ID: 568400). It has been detected in multiple unrelated individuals with connective tissue disorders with variable expressivity and at least one individual who is asymptomatic (Labcorp Genetics (Invitae), GeneDx, CHEO Genetics Diagnostic Laboratory). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.7.0, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM2_Supporting, PP3.