Submissions for variant NM_000548.5(TSC2):c.3611G>A (p.Gly1204Glu)

dbSNP: rs45462194

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000201026	SCV000255894	likely pathogenic	Tuberous sclerosis 2	2015-06-16	criteria provided, single submitter	clinical testing
GeneDx	RCV000414012	SCV000491161	likely pathogenic	not provided	2016-03-24	criteria provided, single submitter	clinical testing	A G1204E variant that is likely pathogenic has been identified in the TSC2 gene. The G1204E variant has been reported previously in association with tuberous sclerosis complex; however, information about parental testing was not provided (Au et al., 2007; vanEeghen et al., 2013; TSC2 LOVD). Functional studies indicate that G1204E is pathogenic (Hoogeveen-Westerveld et al., 2011). 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 G1204E 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 occurs at a position where amino acids with similar properties to Glycine are tolerated across species. Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, missense variants in nearby residues (V1199G, R1200W, P1202H/R, T1203K) have been reported in the Human Gene Mutation Database in association with tuberous sclerosis (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000201026	SCV002230707	pathogenic	Tuberous sclerosis 2	2021-04-20	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects TSC2 protein function (PMID: 21309039). This variant has been observed in individual(s) with clinical features of tuberous sclerosis complex (PMID: 22867869, Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 50148). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with glutamic acid at codon 1204 of the TSC2 protein (p.Gly1204Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid.
CeGaT Center for Human Genetics Tuebingen	RCV000414012	SCV005910142	likely pathogenic	not provided	2025-03-01	criteria provided, single submitter	clinical testing	TSC2: PM2, PM5, PS4:Moderate, PP3, PS3:Supporting
Tuberous sclerosis database (TSC2)	RCV000043416	SCV000067222	not provided	Tuberous sclerosis syndrome		no assertion provided	curation