Submissions for variant NM_000368.5(TSC1):c.167C>T (p.Pro56Leu)

gnomAD frequency: 0.00002  dbSNP: rs750512029

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000444035	SCV000530938	uncertain significance	not provided	2016-08-15	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the TSC1 gene. The P56Lvariant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P56L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Missense variants in nearby residues (L61R, L61P) have been reported in the Human Gene Mutation Database in association with tuberous sclerosis. However, this substitution occurs at a position that is not conserved in species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Ambry Genetics	RCV000564089	SCV000675416	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-10	criteria provided, single submitter	clinical testing	The p.P56L variant (also known as c.167C>T), located in coding exon 2 of the TSC1 gene, results from a C to T substitution at nucleotide position 167. The proline at codon 56 is replaced by leucine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. 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.
Invitae	RCV001088285	SCV000763638	benign	Tuberous sclerosis 1	2024-02-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001088285	SCV002040179	likely benign	Tuberous sclerosis 1	2021-11-07	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004000499	SCV004820360	likely benign	Tuberous sclerosis syndrome	2023-03-23	criteria provided, single submitter	clinical testing