ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.4432G>C (p.Asp1478His) (rs45517343)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414463 SCV000492169 uncertain significance not specified 2016-11-30 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the TCS2 gene. The D1478H variant has been reported previously as an inherited variant in a patient with autism spectrum disorder who did not have any reported history of tuberous sclerosis complex (Bahl et al., 2013). This variant was identified in an individual with tuberous sclerosis complex who also harbored another TSC2 variant (TSC2 Leiden Open Variation Database). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The D1478H 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. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, this substitution occurs at a position where amino acids with similar properties to Aspartic acid are tolerated across species. Additionally, this substitution does not occur within known functional domains of the tuberin protein, where many pathogenic missense variants have been identified (Northrup et al., 2011; Au et al., 2007). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000474980 SCV000544374 uncertain significance Tuberous sclerosis 2 2018-05-23 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with histidine at codon 1478 of the TSC2 protein (p.Asp1478His). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 49925). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Tuberous sclerosis database (TSC2) RCV000043192 SCV000066993 not provided Tuberous sclerosis syndrome no assertion provided curation

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