Submissions for variant NM_000548.5(TSC2):c.5024C>T (p.Pro1675Leu)

dbSNP: rs45483392

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000013201	SCV000544425	pathogenic	Tuberous sclerosis 2	2023-11-02	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1675 of the TSC2 protein (p.Pro1675Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with tuberous sclerosis complex (TSC) (PMID: 9302281, 9463313, 10570911, 11112665, 11520734, 12111193, 15024740, 21520333, 22867869). In at least one individual the variant was observed to be de novo. This variant is also known as 5042C>T and P1657L. ClinVar contains an entry for this variant (Variation ID: 12393). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TSC2 function (PMID: 11290735, 22903760). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000493720	SCV000583057	pathogenic	not provided	2021-05-05	criteria provided, single submitter	clinical testing	Functional studies indicate that P1675L is damaging to the protein (Hoogeveen-Westerveld et al., 2013; Aicher et al., 2001); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 12205112, 28065512, 32211034, 22903760, 11290735, 9302281, 23504366, 15024740, 12136241, 11112665, 25782670, 15121797, 11829138, 22867869, 10205261, 12111193, 27406250, 29801666, 31505689, 32313033)
Athena Diagnostics	RCV000493720	SCV000844589	pathogenic	not provided	2023-08-21	criteria provided, single submitter	clinical testing	This variant has been identified in multiple unrelated individuals with clinical features associated with this gene, including both familial and de novo cases. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 11290735, 22903760)
Genome-Nilou Lab	RCV000013201	SCV002041014	pathogenic	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
3billion	RCV000013201	SCV002318630	pathogenic	Tuberous sclerosis 2	2022-03-22	criteria provided, single submitter	clinical testing	The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 9302281, 11520734, 12111193). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 22903760, 11290735). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.965>=0.6, 3CNET: 0.939>=0.75). It is not observed in the gnomAD v2.1.1 dataset. A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000535873). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Genetics and Molecular Pathology, SA Pathology	RCV000013201	SCV002556815	pathogenic	Tuberous sclerosis 2	2021-03-01	criteria provided, single submitter	clinical testing	The TSC2 c.5024C>T variant is classified as a PATHOGENIC variant (PS3, PS4, PP3, PP4, PP5) The variant is a single nucleotide change from a cytosine to a thymine at position 5024 which is predicted to change the proline at position 1675 in the protein to leucine. The variant is in exon 39 and is located in RAP GTPases activating protein domain of the TSC2 gene. Furthermore, functional studies have shown that this variant decreases TSC2 protein expression levels, disrupts TSC2 phosphorylation, and prevents proper TSC2 protein binding with TSC1 (PMID: 11290735, 22903760) (PS3). The variant is considered as a recurrent change in the TSC2 gene, and has been reported many times in individuals with Tuberous sclerosis in the heterozygous state (PMID:9302281). The variant is in dbSNP (rs45483392) but is absent from population databases (PS4). The variant has been reported in ClinVar (Variation ID: 12393) and HGMD (Accession #: CM971532) as pathogenic (PP5). Computational predictions support a deleterious effect on the gene or gene product (PP3). The phenotype of this patient is highly specific for the TSC2 gene (PP4).
Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University	RCV000013201	SCV002559806	pathogenic	Tuberous sclerosis 2	2022-07-19	criteria provided, single submitter	clinical testing	According to ACMG GL 2015, well-established in vitro functional studies supportive of a damaging effect of this variant (PS3), located in the GAP domain (PM1), absent from controls (PM2), assumed de novo (PM6). Multiple lines of computational evidence support a deleterious effect (PP3), and detected in the patient with clinically definitive tuberous sclerosis complex (PP4) and also reported as pathogenic in LOVD database (PP5).
Ambry Genetics	RCV002345240	SCV002645527	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-08	criteria provided, single submitter	clinical testing	The p.P1675L pathogenic mutation (also known as c.5024C>T), located in coding exon 38 of the TSC2 gene, results from a C to T substitution at nucleotide position 5024. The proline at codon 1675 is replaced by leucine, an amino acid with similar properties. This alteration has been found in multiple individuals who met diagnostic criteria for tuberous sclerosis complex (Ambry internal data; Feng JH et al. Hum. Mutat., 2004 Apr;23:397; Maheshwar MM et al. Hum. Mol. Genet.,1997 Oct;6:1991-6). In addition, in functional studies of the alteration, it was found that the TSC2 signal was significantly reduced compared to the wild-typed TSC1-TSC2 control (Hoogeveen-Westerveld M et al. Hum. Mutat., 2013 Jan;34:167-75). Lastly, further functional studies of this alteration demonstratedreduced phosphorylation and impaired interaction with hamartin (Aicher LD et al. J. Biol. Chem., 2001 Jun;276:21017-21). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics	RCV002496339	SCV002794088	pathogenic	Lymphangiomyomatosis; Isolated focal cortical dysplasia type II; Tuberous sclerosis 2	2021-09-28	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000013201	SCV003823702	pathogenic	Tuberous sclerosis 2	2022-03-14	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000493720	SCV004026007	pathogenic	not provided	2021-11-18	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000493720	SCV004702734	pathogenic	not provided	2023-12-01	criteria provided, single submitter	clinical testing	TSC2: PS2:Very Strong, PM2, PS4:Moderate, PP3, PS3:Supporting
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000013201	SCV004809584	uncertain significance	Tuberous sclerosis 2	2024-04-04	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV002496339	SCV005418727	pathogenic	Lymphangiomyomatosis; Isolated focal cortical dysplasia type II; Tuberous sclerosis 2		criteria provided, single submitter	clinical testing	PM2_Supporting+PS4+PS2+PM5_Supporting+PS3_Moderate+PP3+PP4
OMIM	RCV000013201	SCV000033448	pathogenic	Tuberous sclerosis 2	1997-10-01	no assertion criteria provided	literature only
Tuberous sclerosis database (TSC2)	RCV000043065	SCV000066864	not provided	Tuberous sclerosis syndrome		no assertion provided	curation
Tuberous sclerosis database (TSC2)	RCV000055436	SCV000083657	not provided	Lymphangiomyomatosis		no assertion provided	curation
PreventionGenetics, part of Exact Sciences	RCV004734515	SCV005356881	pathogenic	TSC2-related disorder	2024-05-01	no assertion criteria provided	clinical testing	The TSC2 c.5024C>T variant is predicted to result in the amino acid substitution p.Pro1675Leu. This variant has been reported as causative for tuberous sclerosis, and was found to be de novo in at least one patient (Maheshwar et al. 1997. PubMed ID: 9302281; Dabora et al. 2001. PubMed ID: 11112665; Aicher et al. 2001. PubMed ID: 11290735; Hoogeveen-Westerveld et al. 2013. PubMed ID: 22903760). A functional study showed that this variant affected phosphorylation and reduced interaction with hamartin (Aicher et al. 2001. PubMed ID: 11290735). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.