Submissions for variant NM_000548.5(TSC2):c.4646A>G (p.Tyr1549Cys)

dbSNP: rs45517355

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000412893	SCV000491162	likely pathogenic	not provided	2016-04-18	criteria provided, single submitter	clinical testing	A Y1549C variant that is likely pathogenic has been identified in the TSC2 gene. The Y1549C variant has been reported previously as an assumed pathogenic variant in individuals with TSC (Au et al., 1998; vanEeghen et al., 2013). 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 Y1549C 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. This substitution alters a conserved position in mammals predicted to be within the GAP-related domain of the tuberin protein, (Gumbinger et al., 2009 ), and multiple missense variants at the same and nearby residues have been reported in Human Gene Mutation Database in association with tuberous sclerosis (Stenson et al., 2014), supporting the functional importance of this region of the protein. Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae	RCV001036250	SCV001199602	pathogenic	Tuberous sclerosis 2	2022-06-01	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 1549 of the TSC2 protein (p.Tyr1549Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with tuberous sclerosis complex (PMID: 9463313, 28178598; Invitae). In at least one individual the variant was observed to be de novo. This variant is also known as 4577A>G, Tyr1526Cys. ClinVar contains an entry for this variant (Variation ID: 49479). 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 expected to disrupt TSC2 protein function. This variant disrupts the p.Tyr1549 amino acid residue in TSC2. Other variant(s) that disrupt this residue have been observed in individuals with TSC2-related conditions (PMID: 11112665), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV001036250	SCV002041003	likely pathogenic	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
Tuberous sclerosis database (TSC2)	RCV000042739	SCV000066534	not provided	Tuberous sclerosis syndrome		no assertion provided	curation