ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.3734G>A (p.Arg1245Gln)

gnomAD frequency: 0.00001  dbSNP: rs746588726
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001227098 SCV001399437 benign Tuberous sclerosis 2 2024-10-23 criteria provided, single submitter clinical testing
Ambry Genetics RCV002348765 SCV002621761 uncertain significance Hereditary cancer-predisposing syndrome 2023-11-15 criteria provided, single submitter clinical testing The p.R1245Q variant (also known as c.3734G>A), located in coding exon 30 of the TSC2 gene, results from a G to A substitution at nucleotide position 3734. The arginine at codon 1245 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is well 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003117855 SCV003800824 uncertain significance not specified 2023-01-27 criteria provided, single submitter clinical testing Variant summary: TSC2 c.3734G>A (p.Arg1245Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 249856 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3734G>A in individuals affected with Tuberous Sclerosis Complex and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health RCV004004816 SCV004838396 uncertain significance Tuberous sclerosis syndrome 2023-12-18 criteria provided, single submitter clinical testing This missense variant replaces arginine with glutamine at codon 1245 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 TSC2-related disorders in the literature. This variant has been identified in 1/249856 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.

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