NM_000548.5(TSC2):c.5024C>T (p.Pro1675Leu) AND Tuberous sclerosis 2

Germline classification:: Conflicting interpretations of pathogenicity (8 submissions)
Last evaluated:: Apr 4, 2024
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000013201.42

Allele description [Variation Report for NM_000548.5(TSC2):c.5024C>T (p.Pro1675Leu)]

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

Gene:

TSC2:TSC complex subunit 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16p13.3

Genomic location:

Preferred name:

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

HGVS:

NC_000016.10:g.2087897C>T
NG_005895.1:g.43592C>T
NG_008617.1:g.55324G>A
NM_000548.5:c.5024C>TMANE SELECT
NM_001077183.3:c.4823C>T
NM_001114382.3:c.4955C>T
NM_001318827.2:c.4715C>T
NM_001318829.2:c.4679C>T
NM_001318831.2:c.4292C>T
NM_001318832.2:c.4856C>T
NM_001363528.2:c.4826C>T
NM_001370404.1:c.4892C>T
NM_001370405.1:c.4895C>T
NM_021055.3:c.4895C>T
NP_000539.2:p.Pro1675Leu
NP_001070651.1:p.Pro1608Leu
NP_001107854.1:p.Pro1652Leu
NP_001305756.1:p.Pro1572Leu
NP_001305758.1:p.Pro1560Leu
NP_001305760.1:p.Pro1431Leu
NP_001305761.1:p.Pro1619Leu
NP_001350457.1:p.Pro1609Leu
NP_001357333.1:p.Pro1631Leu
NP_001357334.1:p.Pro1632Leu
NP_066399.2:p.Pro1632Leu
LRG_487t1:c.5024C>T
LRG_487:g.43592C>T
NC_000016.9:g.2137898C>T
NM_000548.3:c.5024C>T
NM_000548.4:c.5024C>T
NM_001318831.1:c.4292C>T
P49815:p.Pro1675Leu
p.(Pro1675Leu)

Protein change:

P1431L; PRO1675LEU

Links:

Tuberous sclerosis database (TSC2): TSC2_00033; UniProtKB: P49815#VAR_009451; OMIM: 191092.0009; dbSNP: rs45483392

NCBI 1000 Genomes Browser:

rs45483392

Molecular consequence:

NM_000548.5:c.5024C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001077183.3:c.4823C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001114382.3:c.4955C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001318827.2:c.4715C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001318829.2:c.4679C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001318831.2:c.4292C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001318832.2:c.4856C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001363528.2:c.4826C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001370404.1:c.4892C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001370405.1:c.4895C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_021055.3:c.4895C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Tuberous sclerosis 2 (TSC2)
Identifiers:: MONDO: MONDO:0013199; MedGen: C1860707; Orphanet: 805; OMIM: 613254

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000033448	OMIM	no assertion criteria provided	Pathogenic (Oct 1, 1997)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000544425	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 2, 2023)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 9302281, 9463313, 10570911, 11112665, 11520734, 12111193, 15024740, 21520333, 22867869, 11290735, 22903760, 28492532
SCV002041014	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 7, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002318630	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 22, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 22903760, 9302281, 11290735, 11520734, 12111193, 25741868
SCV002556815	Genetics and Molecular Pathology, SA Pathology See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 1, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 9302281, 11290735, 22903760, 25741868
SCV002559806	Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 19, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003823702	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 14, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004809584	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 4, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
Japanese	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Germ-line mutational analysis of the TSC2 gene in 90 tuberous-sclerosis patients.

Au KS, Rodriguez JA, Finch JL, Volcik KA, Roach ES, Delgado MR, Rodriguez E Jr, Northrup H.

Am J Hum Genet. 1998 Feb;62(2):286-94.

PubMed [citation]

PMID:: 9463313
PMCID:: PMC1376882

Mutational analysis of TSC1 and TSC2 genes in Japanese patients with tuberous sclerosis complex.

Zhang H, Nanba E, Yamamoto T, Ninomiya H, Ohno K, Mizuguchi M, Takeshita K.

J Hum Genet. 1999;44(6):391-6. Erratum in: J Hum Genet 2000;45(4):269.

PubMed [citation]

PMID:: 10570911

See all PubMed Citations (13)

Details of each submission

From OMIM, SCV000033448.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In 4 unrelated patients with tuberous sclerosis-2 (613254), Maheshwar et al. (1997) identified a C-to-T transition at nucleotide 5042 of the TSC2 gene, which resulted in a proline-to-leucine substitution at codon 1675 (P1675L).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000544425.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome-Nilou Lab, SCV002041014.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From 3billion, SCV002318630.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (6)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Genetics and Molecular Pathology, SA Pathology, SCV002556815.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, SCV002559806.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Japanese	1	not provided	not provided	clinical testing	PubMed (1)

Description

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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV003823702.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV004809584.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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