NM_000548.5(TSC2):c.4323dup (p.Glu1442fs) AND Tuberous sclerosis syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Feb 1, 2019
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:: RCV000042785.5

Allele description [Variation Report for NM_000548.5(TSC2):c.4323dup (p.Glu1442fs)]

NM_000548.5(TSC2):c.4323dup (p.Glu1442fs)

Gene:

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

Variant type:

Duplication

Cytogenetic location:

16p13.3

Genomic location:

Preferred name:

NM_000548.5(TSC2):c.4323dup (p.Glu1442fs)

HGVS:

NC_000016.10:g.2084545dup
NG_005895.1:g.40240dup
NM_000548.5:c.4323dupMANE SELECT
NM_001077183.3:c.4122dup
NM_001114382.3:c.4254dup
NM_001318827.2:c.4014dup
NM_001318829.2:c.3978dup
NM_001318831.2:c.3591dup
NM_001318832.2:c.4155dup
NM_001363528.2:c.4125dup
NM_001370404.1:c.4191dup
NM_001370405.1:c.4194dup
NM_021055.3:c.4194dup
NP_000539.2:p.Glu1442fs
NP_001070651.1:p.Glu1375fs
NP_001107854.1:p.Glu1419fs
NP_001305756.1:p.Glu1339fs
NP_001305758.1:p.Glu1327fs
NP_001305760.1:p.Glu1198fs
NP_001305761.1:p.Glu1386fs
NP_001350457.1:p.Glu1376fs
NP_001357333.1:p.Glu1398fs
NP_001357334.1:p.Glu1399fs
NP_066399.2:p.Glu1399fs
LRG_487t1:c.4323dup
LRG_487:g.40240dup
NC_000016.10:g.2084545_2084546insC
NC_000016.9:g.2134546dup
NM_000548.3:c.4323dupC
p.(Glu1442Argfs*82)

Protein change:

E1198fs

Links:

Tuberous sclerosis database (TSC2): TSC2_01069; dbSNP: rs137854327

Molecular consequence:

NM_000548.5:c.4323dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001077183.3:c.4122dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001114382.3:c.4254dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001318827.2:c.4014dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001318829.2:c.3978dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001318831.2:c.3591dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001318832.2:c.4155dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001363528.2:c.4125dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001370404.1:c.4191dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001370405.1:c.4194dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_021055.3:c.4194dup - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Tuberous sclerosis syndrome (TSC)
Synonyms:: Tuberous sclerosis; Tuberous Sclerosis Complex
Identifiers:: MONDO: MONDO:0001734; MedGen: C0041341; OMIM: PS191100

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000066581	Tuberous sclerosis database (TSC2)	no classification provided (Tuberous Sclerosis Database Assertion Criteria 2015)	not provided	germline	curation	Citation Link,
SCV004848118	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 1, 2019)	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

SCV000066581

Tuberous sclerosis database (TSC2)

no classification provided

(Tuberous Sclerosis Database Assertion Criteria 2015)

not provided

germline

curation

Citation Link,

SCV004848118

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 1, 2019)

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	not provided	not provided	curation
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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 Tuberous sclerosis database (TSC2), SCV000066581.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

#	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 Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848118.1

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

Description

The p.Glu1442fs variant in TSC2 has been previously reported in 1 individual with tuberous sclerosis (LOVD database) and was absent from large population studies. It has been reported in ClinVar (Variation ID 49525). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1442 and leads to a premature termination codon 82 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the TSC2 gene is an established disease mechanism in tuberous sclerosis. In summary, this variant meets criteria to be classified as pathogenic for tuberous sclerosis in an autosomal dominant manner. ACMG/AMP Criteria applied: PVS1, PM2, PS4_P (Richards 2015).

#	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: Apr 12, 2026

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