Submissions for variant NM_000368.5(TSC1):c.1097C>T (p.Pro366Leu)

gnomAD frequency: 0.00001  dbSNP: rs763915012

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000189810	SCV000243459	likely benign	not specified	2016-07-22	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000225784	SCV000284666	benign	Tuberous sclerosis 1	2024-12-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001017276	SCV001178330	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-01	criteria provided, single submitter	clinical testing	The p.P366L variant (also known as c.1097C>T), located in coding exon 9 of the TSC1 gene, results from a C to T substitution at nucleotide position 1097. The proline at codon 366 is replaced by leucine, an amino acid with similar properties. This amino acid position is highly conserved through mammals but not in all 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.
Genome-Nilou Lab	RCV000225784	SCV002040124	likely benign	Tuberous sclerosis 1	2021-11-07	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355439	SCV001550325	uncertain significance	not provided		no assertion criteria provided	clinical testing	The TSC1 p.Pro315Leu variant was not identified in the literature but was identified in dbSNP (ID: rs763915012) and ClinVar (classified as benign by Invitae, likely benign by GeneDx and uncertain significance by Ambry Genetics). The variant was identified in control databases in 2 of 236784 chromosomes at a frequency of 0.000008447 (Genome Aggregation Database March 6, 2019, v2.1.1, non-cancer). The variant was observed in the European (non-Finnish) population in 2 of 102594 chromosomes (freq: 0.000019), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. The p.Pro315 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.