Submissions for variant NM_000548.5(TSC2):c.3818C>T (p.Ala1273Val)

gnomAD frequency: 0.00002  dbSNP: rs749367382

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000441786	SCV000518423	likely benign	not specified	2015-10-09	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.
Invitae	RCV000469602	SCV000544462	benign	Tuberous sclerosis 2	2023-12-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000567292	SCV000675679	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-09	criteria provided, single submitter	clinical testing	The p.A1273V variant (also known as c.3818C>T), located in coding exon 31 of the TSC2 gene, results from a C to T substitution at nucleotide position 3818. The alanine at codon 1273 is replaced by valine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Mayo Clinic Laboratories, Mayo Clinic	RCV001354866	SCV001714533	uncertain significance	not provided	2019-06-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000469602	SCV002039787	likely benign	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000567292	SCV002533458	likely benign	Hereditary cancer-predisposing syndrome	2021-12-22	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001354866	SCV002774870	uncertain significance	not provided	2021-06-29	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001354866	SCV004033433	likely benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing	TSC2: BS2
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354866	SCV001549581	uncertain significance	not provided		no assertion criteria provided	clinical testing	The TSC2 p.Ala1029Val variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs749367382) and ClinVar (classified as uncertain significance by Invitae and Ambry Genetics and as likely benign by GeneDx). The variant was identified in control databases in 6 of 250388 chromosomes (1 homozygous) at a frequency of 0.00002396 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Other in 4 of 6120 chromosomes (freq: 0.000654) and Latino in 2 of 34574 chromosomes (freq: 0.000058), but was not observed in the African, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), or South Asian populations. The p.Ala1029 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.