Submissions for variant NM_000548.5(TSC2):c.3890C>T (p.Ala1297Val)

dbSNP: rs371239156

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000546530	SCV000644483	benign	Tuberous sclerosis 2	2023-12-05	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001121242	SCV001279817	uncertain significance	Tuberous sclerosis syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
CeGaT Center for Human Genetics Tuebingen	RCV001531843	SCV001747144	uncertain significance	not provided	2021-06-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001531843	SCV001803039	uncertain significance	not provided	2019-10-08	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; No data available from control populations to assess the frequency of this variant
Genome-Nilou Lab	RCV000546530	SCV002039792	likely benign	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002358537	SCV002623558	uncertain significance	Hereditary cancer-predisposing syndrome	2024-04-16	criteria provided, single submitter	clinical testing	The p.A1297V variant (also known as c.3890C>T), located in coding exon 32 of the TSC2 gene, results from a C to T substitution at nucleotide position 3890. The alanine at codon 1297 is replaced by valine, 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.
All of Us Research Program, National Institutes of Health	RCV001121242	SCV004821584	uncertain significance	Tuberous sclerosis syndrome	2023-05-23	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 1297 of the TSC2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with tuberous sclerosis complex in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Baylor Genetics	RCV004568834	SCV005054451	uncertain significance	Isolated focal cortical dysplasia type II	2024-03-09	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004541711	SCV004797626	uncertain significance	TSC2-related disorder	2024-02-14	no assertion criteria provided	clinical testing	The TSC2 c.3890C>T variant is predicted to result in the amino acid substitution p.Ala1297Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0011% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.