NM_000548.5(TSC2):c.4544_4547del (p.Asn1515fs) AND Tuberous sclerosis 2

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Sep 15, 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:: RCV000201030.13

Allele description [Variation Report for NM_000548.5(TSC2):c.4544_4547del (p.Asn1515fs)]

NM_000548.5(TSC2):c.4544_4547del (p.Asn1515fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

16p13.3

Genomic location:

Preferred name:

NM_000548.5(TSC2):c.4544_4547del (p.Asn1515fs)

Other names:

p.Asn1515Serfs*60

HGVS:

NC_000016.10:g.2085001_2085004del
NG_005895.1:g.40696_40699del
NM_000548.5:c.4544_4547delMANE SELECT
NM_001077183.3:c.4343_4346del
NM_001114382.3:c.4475_4478del
NM_001318827.2:c.4235_4238del
NM_001318829.2:c.4199_4202del
NM_001318831.2:c.3812_3815del
NM_001318832.2:c.4376_4379del
NM_001363528.2:c.4346_4349del
NM_001370404.1:c.4412_4415del
NM_001370405.1:c.4415_4418del
NM_021055.3:c.4415_4418del
NP_000539.2:p.Asn1515fs
NP_001070651.1:p.Asn1448fs
NP_001107854.1:p.Asn1492fs
NP_001305756.1:p.Asn1412fs
NP_001305758.1:p.Asn1400fs
NP_001305760.1:p.Asn1271fs
NP_001305761.1:p.Asn1459fs
NP_001350457.1:p.Asn1449fs
NP_001357333.1:p.Asn1471fs
NP_001357334.1:p.Asn1472fs
NP_066399.2:p.Asn1472fs
LRG_487:g.40696_40699del
NC_000016.9:g.2134999_2135002del
NC_000016.9:g.2135002_2135005del
NM_000548.3:c.4544_4547delACAA
NM_000548.5:c.4544_4547del
NM_000548.5:c.4544_4547delACAAMANE SELECT
p.(Asn1515Serfs*60)

Protein change:

N1271fs

Links:

Tuberous sclerosis database (TSC2): TSC2_00019; Tuberous sclerosis database (TSC2): TSC2_00590; dbSNP: rs137854175

NCBI 1000 Genomes Browser:

rs137854175

Molecular consequence:

NM_000548.5:c.4544_4547del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001077183.3:c.4343_4346del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001114382.3:c.4475_4478del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001318827.2:c.4235_4238del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001318829.2:c.4199_4202del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001318831.2:c.3812_3815del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001318832.2:c.4376_4379del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001363528.2:c.4346_4349del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001370404.1:c.4412_4415del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001370405.1:c.4415_4418del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_021055.3:c.4415_4418del - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV000255903	Athena Diagnostics Inc	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Dec 19, 2014)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 10607950, 15595939, 26467025
SCV000285408	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 15, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 9302281, 11112665, 12111193, 15595939, 21520333, 10205261, 17304050, 28492532
SCV001364437	Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University	no assertion criteria provided	Pathogenic (Jun 11, 2020)	germline	clinical testing
SCV002041000	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]

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	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
Japanese	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Analysis of all exons of TSC1 and TSC2 genes for germline mutations in Japanese patients with tuberous sclerosis: report of 10 mutations.

Yamashita Y, Ono J, Okada S, Wataya-Kaneda M, Yoshikawa K, Nishizawa M, Hirayama Y, Kobayashi E, Seyama K, Hino O.

Am J Med Genet. 2000 Jan 17;90(2):123-6.

PubMed [citation]

PMID:: 10607950

A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

Karbassi I, Maston GA, Love A, DiVincenzo C, Braastad CD, Elzinga CD, Bright AR, Previte D, Zhang K, Rowland CM, McCarthy M, Lapierre JL, Dubois F, Medeiros KA, Batish SD, Jones J, Liaquat K, Hoffman CA, Jaremko M, Wang Z, Sun W, Buller-Burckle A, et al.

Hum Mutat. 2016 Jan;37(1):127-34. doi: 10.1002/humu.22918. Epub 2015 Oct 29.

PubMed [citation]

PMID:: 26467025
PMCID:: PMC4737317

See all PubMed Citations (11)

Details of each submission

From Athena Diagnostics Inc, SCV000255903.2

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

#	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 Invitae, SCV000285408.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 49304). This premature translational stop signal has been observed in individuals with tuberous sclerosis (PMID: 9302281, 11112665, 12111193, 15595939, 21520333). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asn1515Serfs*60) in the TSC2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TSC2 are known to be pathogenic (PMID: 10205261, 17304050).

#	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 Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, SCV001364437.1

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

From Genome-Nilou Lab, SCV002041000.1

#	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: Feb 28, 2024

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