Submissions for variant NM_000548.5(TSC2):c.3710C>T (p.Ala1237Val)

gnomAD frequency: 0.00004  dbSNP: rs753907159

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001703809	SCV000523848	likely benign	not provided	2021-05-10	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27824329, 31981491)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000964609	SCV001111833	likely benign	Tuberous sclerosis 2	2024-11-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001020951	SCV001182499	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-16	criteria provided, single submitter	clinical testing	The p.A1237V variant (also known as c.3710C>T), located in coding exon 30 of the TSC2 gene, results from a C to T substitution at nucleotide position 3710. The alanine at codon 1237 is replaced by valine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Genome-Nilou Lab	RCV000964609	SCV002039778	likely benign	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235210	SCV003934648	uncertain significance	not specified	2023-05-10	criteria provided, single submitter	clinical testing	Variant summary: TSC2 c.3710C>T (p.Ala1237Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 249992 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3710C>T has been reported in the literature in individuals affected with autism spectrum disorder (de novo occurrence) and neural tube defect (examples: Wang_2016 and Lemay_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Tuberous Sclerosis Complex. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30415495, 31981491, 27824329). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely benign (n=3) and VUS (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004533019	SCV004115024	uncertain significance	TSC2-related disorder	2023-06-01	criteria provided, single submitter	clinical testing	The TSC2 c.3710C>T variant is predicted to result in the amino acid substitution p.Ala1237Val. This variant has been reported de novo in an individual with autism spectrum disorder (Table S6, Wang et al. 2016. PubMed ID: 27824329; Table S6, Satterstrom et al. 2020. PubMed ID: 31981491). This variant is reported in 7 of 250,000 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/16-2131695-C-T). It has conflicting interpretations of likely benign and uncertain significance (https://preview.ncbi.nlm.nih.gov/clinvar/variation/383442/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Myriad Genetics, Inc.	RCV000964609	SCV005405992	likely benign	Tuberous sclerosis 2	2024-08-16	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.