NM_000548.5(TSC2):c.4643T>C (p.Leu1548Pro) AND Tuberous sclerosis 2

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 28, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003512006.2

Allele description [Variation Report for NM_000548.5(TSC2):c.4643T>C (p.Leu1548Pro)]

NM_000548.5(TSC2):c.4643T>C (p.Leu1548Pro)

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.4643T>C (p.Leu1548Pro)

HGVS:

NC_000016.10:g.2085303T>C
NG_005895.1:g.40998T>C
NM_000548.5:c.4643T>CMANE SELECT
NM_001077183.3:c.4442T>C
NM_001114382.3:c.4574T>C
NM_001318827.2:c.4334T>C
NM_001318829.2:c.4298T>C
NM_001318831.2:c.3911T>C
NM_001318832.2:c.4475T>C
NM_001363528.2:c.4445T>C
NM_001370404.1:c.4511T>C
NM_001370405.1:c.4514T>C
NM_021055.3:c.4514T>C
NP_000539.2:p.Leu1548Pro
NP_001070651.1:p.Leu1481Pro
NP_001107854.1:p.Leu1525Pro
NP_001305756.1:p.Leu1445Pro
NP_001305758.1:p.Leu1433Pro
NP_001305760.1:p.Leu1304Pro
NP_001305761.1:p.Leu1492Pro
NP_001350457.1:p.Leu1482Pro
NP_001357333.1:p.Leu1504Pro
NP_001357334.1:p.Leu1505Pro
NP_066399.2:p.Leu1505Pro
LRG_487t1:c.4643T>C
LRG_487:g.40998T>C
NC_000016.9:g.2135304T>C
NM_000548.3:c.4643T>C
p.(Leu1548Pro)

Protein change:

L1304P

Links:

Tuberous sclerosis database (TSC2): TSC2_01249; dbSNP: rs397515070

NCBI 1000 Genomes Browser:

rs397515070

Molecular consequence:

NM_000548.5:c.4643T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001077183.3:c.4442T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001114382.3:c.4574T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001318827.2:c.4334T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001318829.2:c.4298T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001318831.2:c.3911T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001318832.2:c.4475T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001363528.2:c.4445T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001370404.1:c.4511T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001370405.1:c.4514T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_021055.3:c.4514T>C - missense variant - [Sequence Ontology: SO:0001583]

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
SCV004296675	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 28, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 21309039, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004296675

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 28, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Functional assessment of variants in the TSC1 and TSC2 genes identified in individuals with Tuberous Sclerosis Complex.

Hoogeveen-Westerveld M, Wentink M, van den Heuvel D, Mozaffari M, Ekong R, Povey S, den Dunnen JT, Metcalfe K, Vallee S, Krueger S, Bergoffen J, Shashi V, Elmslie F, Kwiatkowski D, Sampson J, Vidales C, Dzarir J, Garcia-Planells J, Dies K, Maat-Kievit A, van den Ouweland A, Halley D, et al.

Hum Mutat. 2011 Apr;32(4):424-35. doi: 10.1002/humu.21451. Epub 2011 Mar 8.

PubMed [citation]

PMID:: 21309039

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004296675.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1548 of the TSC2 protein (p.Leu1548Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of TSC2-related conditions (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 65095). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TSC2 protein function. Experimental studies have shown that this missense change affects TSC2 function (PMID: 21309039). 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

Last Updated: Sep 29, 2024

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