NM_000548.5(TSC2):c.4839CAT[1] (p.Ile1614del) AND Tuberous sclerosis 2

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Feb 23, 2023
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:: RCV000201210.9

Allele description [Variation Report for NM_000548.5(TSC2):c.4839CAT[1] (p.Ile1614del)]

NM_000548.5(TSC2):c.4839CAT[1] (p.Ile1614del)

Gene:

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

Variant type:

Microsatellite

Cytogenetic location:

16p13.3

Genomic location:

Preferred name:

NM_000548.5(TSC2):c.4839CAT[1] (p.Ile1614del)

HGVS:

NC_000016.10:g.2086369CAT[1]
NG_005895.1:g.42064CAT[1]
NM_000548.5:c.4839CAT[1]MANE SELECT
NM_001077183.3:c.4638CAT[1]
NM_001114382.3:c.4770CAT[1]
NM_001318827.2:c.4530CAT[1]
NM_001318829.2:c.4494CAT[1]
NM_001318831.2:c.4107CAT[1]
NM_001318832.2:c.4671CAT[1]
NM_001363528.2:c.4641CAT[1]
NM_001370404.1:c.4707CAT[1]
NM_001370405.1:c.4710CAT[1]
NM_021055.3:c.4710CAT[1]
NP_000539.2:p.Ile1614del
NP_001070651.1:p.Ile1547del
NP_001107854.1:p.Ile1591del
NP_001305756.1:p.Ile1511del
NP_001305758.1:p.Ile1499del
NP_001305760.1:p.Ile1370del
NP_001305761.1:p.Ile1558del
NP_001350457.1:p.Ile1548del
NP_001357333.1:p.Ile1570del
NP_001357334.1:p.Ile1571del
NP_066399.2:p.Ile1571del
LRG_487:g.42064CAT[1]
NC_000016.9:g.2136370CAT[1]
NC_000016.9:g.2136370_2136372del
NM_000548.3:c.4842_4844delCAT
NM_000548.5:c.4842_4844delMANE SELECT
p.(Ile1614del)

Protein change:

I1370del

Links:

Tuberous sclerosis database (TSC2): TSC2_00118; dbSNP: rs137854331

NCBI 1000 Genomes Browser:

rs137854331

Molecular consequence:

NM_000548.5:c.4839CAT[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001077183.3:c.4638CAT[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001114382.3:c.4770CAT[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001318827.2:c.4530CAT[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001318829.2:c.4494CAT[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001318831.2:c.4107CAT[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001318832.2:c.4671CAT[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001363528.2:c.4641CAT[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001370404.1:c.4707CAT[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001370405.1:c.4710CAT[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_021055.3:c.4710CAT[1] - inframe_deletion - [Sequence Ontology: SO:0001822]

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
SCV001222548	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 7, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 9463313, 22748302, 28492532
SCV003841872	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 23, 2023)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 22748302, 9463313, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001222548

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 7, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV003841872

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 23, 2023)

unknown

clinical testing

PubMed (3)
[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
not provided	unknown	yes	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

Uterine angiosarcoma associated with lymphangioleiomyomatosis in a patient with tuberous sclerosis complex: an autopsy case report with immunohistochemical and genetic analysis.

Hayashi T, Koike K, Kumasaka T, Saito T, Mitani K, Terao Y, Ogishima D, Yao T, Takeda S, Takahashi K, Seyama K.

Hum Pathol. 2012 Oct;43(10):1777-84. doi: 10.1016/j.humpath.2012.03.020. Epub 2012 Jun 27.

PubMed [citation]

PMID:: 22748302

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001222548.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

ClinVar contains an entry for this variant (Variation ID: 49325). This variant is also known as del (4770-4772); dl Ile 1591. This variant has been observed in individual(s) with tuberous sclerosis complex (PMID: 9463313, 22748302; Invitae). This variant is not present in population databases (gnomAD no frequency). This variant, c.4842_4844del, results in the deletion of 1 amino acid(s) of the TSC2 protein (p.Ile1614del), but otherwise preserves the integrity of the reading frame. 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 3billion, SCV003841872.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The variant is not observed in the gnomAD v2.1.1 dataset. Inframe deletion located in a nonrepeat region was predicted to change the length of the protein and disrupt normal protein function. The variant has been observed in at least two similarly affected unrelated individuals (PMID: 22748302, 9463313). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000049325 / PMID: 9463313). 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	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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