ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.4998C>A (p.Phe1666Leu)

gnomAD frequency: 0.00001  dbSNP: rs757221445
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189938 SCV000243605 uncertain significance not provided 2020-03-05 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics RCV000575063 SCV000664616 uncertain significance Hereditary cancer-predisposing syndrome 2022-09-02 criteria provided, single submitter clinical testing The p.F1666L variant (also known as c.4998C>A), located in coding exon 38 of the TSC2 gene, results from a C to A substitution at nucleotide position 4998. The phenylalanine at codon 1666 is replaced by leucine, an amino acid with highly 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV001088052 SCV000765950 likely benign Tuberous sclerosis 2 2025-01-17 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV001088052 SCV002040240 likely benign Tuberous sclerosis 2 2021-11-07 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000575063 SCV002533998 uncertain significance Hereditary cancer-predisposing syndrome 2022-01-12 criteria provided, single submitter curation
All of Us Research Program, National Institutes of Health RCV003996871 SCV004827788 uncertain significance Tuberous sclerosis syndrome 2024-06-09 criteria provided, single submitter clinical testing This missense variant replaces phenylalanine with leucine at codon 1666 of the TSC2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 3/280940 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 RCV005016536 SCV005638946 uncertain significance Lymphangiomyomatosis; Isolated focal cortical dysplasia type II; Tuberous sclerosis 2 2024-02-12 criteria provided, single submitter clinical testing

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