Submissions for variant NM_000548.5(TSC2):c.4952A>G (p.Asn1651Ser)

dbSNP: rs45517382

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000359328	SCV000329791	pathogenic	not provided	2022-02-01	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect as N1651S impairs the ability of tuberin to act as a GTPase activating protein (Tee et al., 2003); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 18032745, 11741833, 11112665, 18411301, 22055460, 12906785, 1846615, 27078846, 18550814, 15798777, 14718525, 21252315, 15024740, 9302281, 11521203, 27974549, 12111193, 10205261)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000543686	SCV000644583	pathogenic	Tuberous sclerosis 2	2024-04-01	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 1651 of the TSC2 protein (p.Asn1651Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with tuberous sclerosis (PMID: 9302281, 12111193, 15024740). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 49335). 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 TSC2 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects TSC2 function (PMID: 12906785, 14718525, 18411301, 18550814, 27078846). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000543686	SCV002041010	pathogenic	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002336159	SCV002642642	pathogenic	Hereditary cancer-predisposing syndrome	2017-05-15	criteria provided, single submitter	clinical testing	The p.N1651S pathogenic mutation (also known as c.4952A>G), located in coding exon 37 of the TSC2 gene, results from an A to G substitution at nucleotide position 4952. The asparagine at codon 1651 is replaced by serine, an amino acid with highly similar properties. This mutation was detected as a de novo occurrence (paternity and maternity confirmed) in an individual who fulfilled diagnostic criteria for tuberous sclerosis complex (TSC). The mutation was also detected in this individual's two sons with TSC; however, it was not identified in his third unaffected son (Maheshwar MM et al. Hum. Mol. Genet., 1997 Oct;6:1991-6). In addition, this mutation has been detected in several individuals meeting formal diagnostic criteria for TSC (Jones AC et al. Am. J. Hum. Genet., 1999 May;64:1305-15; Dabora SL et al. Am. J. Hum. Genet., 2001 Jan;68:64-80; Langkau N et al. Eur. J. Pediatr., 2002 Jul;161:393-402; Zhao XY et al. Br. J. Dermatol., 2006 Nov;155:1070-3; Kamimura T et al. Epilepsia, 2006 Jun;47:991-7). In one other study, this mutation was shown to impair the ability of tuberin to act as a GTPase enhancing protein (Tee AR et al. Curr. Biol., 2003 Aug;13:1259-68). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000543686	SCV005417285	pathogenic	Tuberous sclerosis 2		criteria provided, single submitter	clinical testing	PM2_Supporting+PS4_Moderate+PS2+PP1+PP4+PP3_Moderate
Tuberous sclerosis database (TSC2)	RCV000042595	SCV000066389	not provided	Tuberous sclerosis syndrome		no assertion provided	curation
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000042595	SCV000805048	likely pathogenic	Tuberous sclerosis syndrome	2016-08-09	no assertion criteria provided	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000359328	SCV003839177	pathogenic	not provided	2022-03-17	no assertion criteria provided	clinical testing	DNA sequence analysis of the TSC2 gene demonstrated a sequence change, c.4952A>G, in exon 38 that results in an amino acid change, p.Asn1651Ser. The p.Asn1651Ser change affects a highly conserved amino acid residue located in a domain of the TSC2 protein that is known to be functional. This sequence change has previously been described in multiple individuals with TSC2-related tuberous sclerosis complex (PMID: 9302281, 12111193, 15024740) and has not been described in population databases such as ExAC and gnomAD. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide mostly deleterious results for the p.Asn1651Ser substitution. Functional studies have demonstrated that this sequence change impacts the function of the TSC2 protein (PMID: 12906785, 18411301, 14718525, 18550814, 27078846). The p.Asn1651Ser amino acid change occurs in a region of the TSC2 gene where other missense sequence changes have been described in individuals with TSC2-related disorders including a missense change at the same position (p.Asn1651Thr, PMID: 32211034). Based on these evidences, this sequence change is classified as pathogenic.