ClinVar Miner

Submissions for variant NM_000368.5(TSC1):c.2077G>C (p.Asp693His)

gnomAD frequency: 0.00002  dbSNP: rs397514800
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000724243 SCV000226569 uncertain significance not provided 2014-12-15 criteria provided, single submitter clinical testing
GeneDx RCV000724243 SCV000243506 likely benign not provided 2020-04-07 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 22161988, 21309039)
Labcorp Genetics (formerly Invitae), Labcorp RCV001083507 SCV000284694 benign Tuberous sclerosis 1 2024-01-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000564681 SCV000675370 likely benign Hereditary cancer-predisposing syndrome 2018-09-17 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.
Genome-Nilou Lab RCV001083507 SCV002040065 likely benign Tuberous sclerosis 1 2021-11-07 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000564681 SCV002530957 uncertain significance Hereditary cancer-predisposing syndrome 2022-01-21 criteria provided, single submitter curation
PreventionGenetics, part of Exact Sciences RCV003407435 SCV004107288 uncertain significance TSC1-related disorder 2023-03-02 criteria provided, single submitter clinical testing The TSC1 c.2077G>C variant is predicted to result in the amino acid substitution p.Asp693His. Functional studies of this variant by immunoblot analysis were inconclusive (Table 1, Hoogeveen-Westerveld et al. 2012. PubMed ID: 22161988). This variant is reported in 1 of ~251,000 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/9-135779169-C-G) and has conflicting interpretations of benign, likely benign, and uncertain significance (https://preview.ncbi.nlm.nih.gov/clinvar/variation/64734/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health RCV000054914 SCV004840459 uncertain significance Tuberous sclerosis syndrome 2023-12-01 criteria provided, single submitter clinical testing This missense variant replaces aspartic acid with histidine at codon 693 of the TSC1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown that the variant did not affect TSC1 stability, TSC1/TSC2 complex interaction or mTORC1 activity (PMID: 22161988). To our knowledge, this variant has not been reported in individuals affected with tuberous sclerosis complex in the literature. This variant has been identified in 1/251234 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.
Tuberous sclerosis database (TSC1) RCV000054914 SCV000083129 not provided Tuberous sclerosis syndrome no assertion provided curation

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