NM_000548.5(TSC2):c.127G>A (p.Glu43Lys) AND Tuberous sclerosis 2

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Nov 7, 2021
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001071459.17

Allele description [Variation Report for NM_000548.5(TSC2):c.127G>A (p.Glu43Lys)]

NM_000548.5(TSC2):c.127G>A (p.Glu43Lys)

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.127G>A (p.Glu43Lys)

HGVS:

NC_000016.10:g.2048742G>A
NG_005895.1:g.4437G>A
NG_008412.1:g.4125C>T
NM_000548.5:c.127G>AMANE SELECT
NM_001077183.3:c.127G>A
NM_001114382.3:c.127G>A
NM_001318827.2:c.127G>A
NM_001318829.2:c.-10+677G>A
NM_001318831.2:c.-100G>A
NM_001318832.2:c.160G>A
NM_001363528.2:c.127G>A
NM_001370404.1:c.127G>A
NM_001370405.1:c.127G>A
NM_021055.3:c.127G>A
NP_000539.2:p.Glu43Lys
NP_001070651.1:p.Glu43Lys
NP_001107854.1:p.Glu43Lys
NP_001305756.1:p.Glu43Lys
NP_001305761.1:p.Glu54Lys
NP_001350457.1:p.Glu43Lys
NP_001357333.1:p.Glu43Lys
NP_001357334.1:p.Glu43Lys
NP_066399.2:p.Glu43Lys
LRG_487t1:c.127G>A
LRG_1366:g.4125C>T
LRG_487:g.4437G>A
NC_000016.9:g.2098743G>A
NM_000548.3:c.127G>A

Protein change:

E43K

Links:

dbSNP: rs2084685904

NCBI 1000 Genomes Browser:

rs2084685904

Molecular consequence:

NM_001318831.2:c.-100G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001318829.2:c.-10+677G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000548.5:c.127G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001077183.3:c.127G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001114382.3:c.127G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001318827.2:c.127G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001318832.2:c.160G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001363528.2:c.127G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001370404.1:c.127G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001370405.1:c.127G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_021055.3:c.127G>A - 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
SCV001236765	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Apr 25, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002040524	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 7, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001236765

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Apr 25, 2019)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002040524

Genome-Nilou Lab

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 7, 2021)

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	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001236765.5

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

Description

This variant is not present in population databases (ExAC no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with TSC2-related conditions. This sequence change replaces glutamic acid with lysine at codon 43 of the TSC2 protein (p.Glu43Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine.

#	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, SCV002040524.1

#	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

Last Updated: Oct 26, 2024

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