ClinVar Miner

Submissions for variant NM_000368.5(TSC1):c.1811A>G (p.Tyr604Cys)

gnomAD frequency: 0.00001  dbSNP: rs1057522817
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000436287 SCV000529612 uncertain significance not provided 2016-07-14 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the TSC1 gene. The Y604C variant has not been publishedas a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed inapproximately 6,500 individuals of European and African American ancestry in the NHLBI Exome SequencingProject, indicating it is not a common benign variant in these populations. The Y604C variant is a non-conservativeamino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity,charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and insilico analysis predicts this variant is probably damaging to the protein structure/function. However, the vast majorityof TSC1 pathogenic variants result in protein truncation, while missense variants have been reported only rarely(Northrup et al., 2011; Au et al., 2007). Therefore, based on the currently available information, it is unclear whetherthis variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp RCV000548490 SCV000641524 uncertain significance Tuberous sclerosis 1 2023-12-22 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 604 of the TSC1 protein (p.Tyr604Cys). This variant is present in population databases (no rsID available, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with TSC1-related conditions. ClinVar contains an entry for this variant (Variation ID: 387536). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TSC1 protein function with a negative predictive value of 80%. 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.
Genome-Nilou Lab RCV000548490 SCV002041363 uncertain significance Tuberous sclerosis 1 2021-11-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV002411368 SCV002713244 uncertain significance Hereditary cancer-predisposing syndrome 2024-04-26 criteria provided, single submitter clinical testing The p.Y604C variant (also known as c.1811A>G), located in coding exon 13 of the TSC1 gene, results from an A to G substitution at nucleotide position 1811. The tyrosine at codon 604 is replaced by cysteine, an amino acid with highly dissimilar 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.
Fulgent Genetics, Fulgent Genetics RCV002481320 SCV002791565 uncertain significance Lymphangiomyomatosis; Tuberous sclerosis 1; Isolated focal cortical dysplasia type II 2021-12-16 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV004000473 SCV004832710 uncertain significance Tuberous sclerosis syndrome 2024-04-10 criteria provided, single submitter clinical testing This missense variant replaces tyrosine with cysteine at codon 604 of the TSC1 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 TSC1-related disorders in the literature. This variant has been identified in 1/31392 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.
Baylor Genetics RCV004567920 SCV005054391 uncertain significance Isolated focal cortical dysplasia type II 2024-03-20 criteria provided, single submitter clinical testing

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