ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.374A>G (p.Lys125Arg)

gnomAD frequency: 0.00002  dbSNP: rs767059758
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000550667 SCV000644472 benign Tuberous sclerosis 2 2024-01-16 criteria provided, single submitter clinical testing
Ambry Genetics RCV001021036 SCV001182599 likely benign Hereditary cancer-predisposing syndrome 2020-05-01 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Illumina Laboratory Services, Illumina RCV001115885 SCV001273900 uncertain significance Tuberous sclerosis syndrome 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx RCV001591241 SCV001826592 likely benign not provided 2020-11-03 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000550667 SCV002041061 likely benign Tuberous sclerosis 2 2021-11-07 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV001021036 SCV002533447 uncertain significance Hereditary cancer-predisposing syndrome 2021-06-16 criteria provided, single submitter curation
Johns Hopkins Genomics, Johns Hopkins University RCV000550667 SCV002570268 likely benign Tuberous sclerosis 2 2022-04-04 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV001115885 SCV004816952 uncertain significance Tuberous sclerosis syndrome 2023-11-30 criteria provided, single submitter clinical testing This missense variant replaces lysine with arginine at codon 125 of the TSC2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with tuberous sclerosis complex in the literature. This variant has been identified in 3/282878 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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