Submissions for variant NM_000548.5(TSC2):c.2355G>A (p.Gln785=)

dbSNP: rs2088708544

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001036320	SCV001199675	pathogenic	Tuberous sclerosis 2	2024-03-11	criteria provided, single submitter	clinical testing	This sequence change affects codon 785 of the TSC2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the TSC2 protein. This variant also falls at the last nucleotide of exon 21, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with tuberous sclerosis complex (PMID: 21520333, 34403804, 35918040). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 835435). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV001509506	SCV001716254	uncertain significance	not provided	2020-12-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001036320	SCV002040693	uncertain significance	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001509506	SCV004221416	likely pathogenic	not provided	2021-08-13	criteria provided, single submitter	clinical testing	This synonymous variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with tuberous sclerosis complex (TSC) (PMID: 34403804 (2021), 35918040 (2022)). Internal laboratory data indicates this variant appears to segregate with disease in at least one family. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper TSC2 mRNA splicing. Based on the available information, this variant is classified as likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005056807	SCV005040380	pathogenic	Tuberous sclerosis syndrome	2024-11-26	criteria provided, single submitter	clinical testing	Variant summary: TSC2 c.2355G>A (p.Gln785Gln) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant weakens the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250650 control chromosomes. c.2355G>A has been reported in the literature in multiple individuals affected with Tuberous Sclerosis Complex (e.g. Babol-Pokora_2021, Ng_2022). It has also been reported among multiple probands and/or affected family members in the LOVD database. These data indicate that the variant is very likely to be associated with disease. 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: 34403804, 35918040, LOVD database). ClinVar contains an entry for this variant (Variation ID: 835435). Based on the evidence outlined above, the variant was classified as pathogenic.
3billion	RCV001036320	SCV005903728	uncertain significance	Tuberous sclerosis 2	2023-06-12	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Synonymous variant predicted to alter splicing (see below). In silico tools predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 0.87). The variant has been reported to be associated with TSC2-related disorder (PMID: 34403804). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline.