ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.1154A>G (p.His385Arg)

gnomAD frequency: 0.00001  dbSNP: rs757353933
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000570261 SCV000675768 uncertain significance Hereditary cancer-predisposing syndrome 2024-04-03 criteria provided, single submitter clinical testing The p.H385R variant (also known as c.1154A>G), located in coding exon 11 of the TSC2 gene, results from an A to G substitution at nucleotide position 1154. The histidine at codon 385 is replaced by arginine, 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. Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV001054845 SCV001219200 benign Tuberous sclerosis 2 2024-09-18 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV001054845 SCV002040593 uncertain significance Tuberous sclerosis 2 2021-11-07 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV004001174 SCV004828786 uncertain significance Tuberous sclerosis syndrome 2023-11-30 criteria provided, single submitter clinical testing This missense variant replaces histidine with arginine at codon 385 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 2/251294 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.
Fulgent Genetics, Fulgent Genetics RCV005019000 SCV005644966 likely benign Lymphangiomyomatosis; Isolated focal cortical dysplasia type II; Tuberous sclerosis 2 2024-06-19 criteria provided, single submitter clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV001054845 SCV005689349 uncertain significance Tuberous sclerosis 2 2024-08-06 criteria provided, single submitter clinical testing The TSC2 c.1154A>G (p.His385Arg) missense change has a maximum subpopulation frequency of 0.0009% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. To our knowledge, this variant has not been reported in individuals with tuberous sclerosis complex. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.

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