Submissions for variant NM_000548.5(TSC2):c.1820C>T (p.Ala607Val)

gnomAD frequency: 0.00005  dbSNP: rs397515296

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000464888	SCV000515654	likely benign	not provided	2019-11-13	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24728327, 26691941)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001086928	SCV000544347	likely benign	Tuberous sclerosis 2	2025-01-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000561143	SCV000675490	likely benign	Hereditary cancer-predisposing syndrome	2019-09-19	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000122208	SCV001339170	uncertain significance	not specified	2020-03-26	criteria provided, single submitter	clinical testing	Variant summary: TSC2 c.1820C>T (p.Ala607Val) results in a non-conservative amino acid change located in the Tuberin-type domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 250358 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in TSC2 causing Tuberous Sclerosis Complex (4e-05 vs 6.9e-05), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1820C>T in individuals affected with Tuberous Sclerosis Complex and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, two classify as likely benign while two classify as VUS. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome-Nilou Lab	RCV001086928	SCV002039579	likely benign	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000561143	SCV002531006	likely benign	Hereditary cancer-predisposing syndrome	2021-11-19	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV003997361	SCV004819323	uncertain significance	Tuberous sclerosis syndrome	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 607 of the TSC2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 been identified in 12/281766 chromosomes 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.
ITMI	RCV000122208	SCV000086429	not provided	not specified	2013-09-19	no assertion provided	reference population