ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.1928A>G (p.Tyr643Cys)

gnomAD frequency: 0.00002  dbSNP: rs1319342312
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000803397 SCV000943266 benign Tuberous sclerosis 2 2024-01-19 criteria provided, single submitter clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV001526823 SCV001737478 uncertain significance Tuberous sclerosis syndrome 2021-05-27 criteria provided, single submitter clinical testing The TSC2 c.1928A>G (p.Tyr643Cys) missense change has a maximum subpopulation frequency of 0.0040% in gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org/variant/16-2121599-A-G?dataset=gnomad_r2_1). Seven of seven in silico tools predict a deleterious effect of this variant on protein function (PP3), but to our knowledge these predictions have not been confirmed by functional assays. To our knowledge, this variant has not been reported in individuals with tuberous sclerosis complex. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_Supporting, PP3.
GeneDx RCV001592994 SCV001817357 uncertain significance not provided 2022-07-20 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Observed in 0.0007% (2/281658 alleles) in large population cohorts (gnomAD)
Genome-Nilou Lab RCV000803397 SCV002040651 uncertain significance Tuberous sclerosis 2 2021-11-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV002406784 SCV002719854 uncertain significance Hereditary cancer-predisposing syndrome 2022-04-20 criteria provided, single submitter clinical testing The p.Y643C variant (also known as c.1928A>G), located in coding exon 17 of the TSC2 gene, results from an A to G substitution at nucleotide position 1928. The tyrosine at codon 643 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 RCV002501080 SCV002786692 uncertain significance Lymphangiomyomatosis; Isolated focal cortical dysplasia type II; Tuberous sclerosis 2 2022-03-14 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003396403 SCV004111966 uncertain significance TSC2-related condition 2023-02-25 criteria provided, single submitter clinical testing The TSC2 c.1928A>G variant is predicted to result in the amino acid substitution p.Tyr643Cys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-2121599-A-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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