ClinVar Miner

Submissions for variant NM_000368.5(TSC1):c.941C>T (p.Thr314Met)

gnomAD frequency: 0.00003  dbSNP: rs373454700
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130736 SCV000185627 likely benign Hereditary cancer-predisposing syndrome 2021-05-04 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.
GeneDx RCV000726223 SCV000243522 uncertain significance not provided 2014-10-24 criteria provided, single submitter clinical testing p.Thr314Met (ACG>ATG): c.941 C>T in exon 10 of the TSC1 gene (NM_000368.4). The T314M variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The T314M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved across species, and in silico analysis is inconsistent in its predictions as to whether or not the R314M variant is damaging to the protein structure/function. Additionally, the vast majority of TSC1 mutations result in protein truncation, while missense mutations have been reported only rarely (Northrup et al., 2011; Au et al., 2007). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Eurofins Ntd Llc (ga) RCV000726223 SCV000342999 uncertain significance not provided 2016-07-08 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001084392 SCV000641680 likely benign Tuberous sclerosis 1 2024-01-24 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000764813 SCV000895964 uncertain significance Lymphangiomyomatosis; Tuberous sclerosis 1; Isolated focal cortical dysplasia type II 2018-10-31 criteria provided, single submitter clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV000726223 SCV002009233 uncertain significance not provided 2021-11-03 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV001084392 SCV002040134 uncertain significance Tuberous sclerosis 1 2021-11-07 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000130736 SCV002531499 uncertain significance Hereditary cancer-predisposing syndrome 2021-04-14 criteria provided, single submitter curation
All of Us Research Program, National Institutes of Health RCV003998074 SCV004840508 uncertain significance Tuberous sclerosis syndrome 2024-08-06 criteria provided, single submitter clinical testing This missense variant replaces threonine with methionine at codon 314 of the TSC1 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 TSC1-related disorders in the literature. This variant has been identified in 4/282178 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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