NM_000548.5(TSC2):c.5228G>A (p.Arg1743Gln) AND Tuberous sclerosis 2

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Jan 20, 2024
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:: RCV000201149.18

Allele description [Variation Report for NM_000548.5(TSC2):c.5228G>A (p.Arg1743Gln)]

NM_000548.5(TSC2):c.5228G>A (p.Arg1743Gln)

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.5228G>A (p.Arg1743Gln)

Other names:

p.R1743Q:CGG>CAG

HGVS:

NC_000016.10:g.2088294G>A
NG_005895.1:g.43989G>A
NG_008617.1:g.54927C>T
NM_000548.5:c.5228G>AMANE SELECT
NM_001077183.3:c.5027G>A
NM_001114382.3:c.5159G>A
NM_001318827.2:c.4919G>A
NM_001318829.2:c.4883G>A
NM_001318831.2:c.4496G>A
NM_001318832.2:c.5060G>A
NM_001363528.2:c.5030G>A
NM_001370404.1:c.5096G>A
NM_001370405.1:c.5087G>A
NM_021055.3:c.5099G>A
NP_000539.2:p.Arg1743Gln
NP_001070651.1:p.Arg1676Gln
NP_001107854.1:p.Arg1720Gln
NP_001305756.1:p.Arg1640Gln
NP_001305758.1:p.Arg1628Gln
NP_001305760.1:p.Arg1499Gln
NP_001305761.1:p.Arg1687Gln
NP_001350457.1:p.Arg1677Gln
NP_001357333.1:p.Arg1699Gln
NP_001357334.1:p.Arg1696Gln
NP_066399.2:p.Arg1700Gln
LRG_487t1:c.5228G>A
LRG_487:g.43989G>A
NC_000016.9:g.2138295G>A
NM_000548.3:c.5228G>A
NM_000548.4:c.5228G>A
P49815:p.Arg1743Gln
p.(Arg1743Gln)

Protein change:

R1499Q

Links:

Tuberous sclerosis database (TSC2): TSC2_00096; UniProtKB: P49815#VAR_008031; dbSNP: rs45507199

NCBI 1000 Genomes Browser:

rs45507199

Molecular consequence:

NM_000548.5:c.5228G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001077183.3:c.5027G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001114382.3:c.5159G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001318827.2:c.4919G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001318829.2:c.4883G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001318831.2:c.4496G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001318832.2:c.5060G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001363528.2:c.5030G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001370404.1:c.5096G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001370405.1:c.5087G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_021055.3:c.5099G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000544537	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 20, 2024)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 10732801, 16114042, 20165957, 21309039, 10205261, 16981987, 18854862, 25782670, 28492532
SCV001423576	Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 10, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001425281	Molecular Biology Laboratory, Fundació Puigvert - KidneyPanel_2020	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 1, 2020)	germline	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 33532864
SCV002041028	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 7, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005417109	Juno Genomics, Hangzhou Juno Genomics, Inc	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	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	not provided	not provided	not provided	not provided	not provided	clinical testing, research
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
Japanese	germline	yes	2	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutation and polymorphism analysis in the tuberous sclerosis 2 (TSC2) gene.

Gilbert JR, Guy V, Kumar A, Wolpert C, Kandt R, Aylesworth A, Roses AD, Pericak-Vance MA.

Neurogenetics. 1998 Aug;1(4):267-72.

PubMed [citation]

PMID:: 10732801

Analysis of 65 tuberous sclerosis complex (TSC) patients by TSC2 DGGE, TSC1/TSC2 MLPA, and TSC1 long-range PCR sequencing, and report of 28 novel mutations.

Rendtorff ND, Bjerregaard B, Frödin M, Kjaergaard S, Hove H, Skovby F, Brøndum-Nielsen K, Schwartz M; Danish Tuberous Sclerosis Group.

Hum Mutat. 2005 Oct;26(4):374-83.

PubMed [citation]

PMID:: 16114042

See all PubMed Citations (11)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000544537.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1743 of the TSC2 protein (p.Arg1743Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with tuberous sclerosis (PMID: 10732801, 16114042, 18854862, 20165957, 21309039). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 49960). 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: 18854862, 21309039). This variant disrupts the p.Arg1743 amino acid residue in TSC2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10205261, 16981987, 18854862, 25782670). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, SCV001423576.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Japanese	2	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	yes	not provided	not provided	not provided		2	not provided	not provided	not provided

From Molecular Biology Laboratory, Fundació Puigvert - KidneyPanel_2020, SCV001425281.1

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

#	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 Genome-Nilou Lab, SCV002041028.1

#	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

From Juno Genomics, Hangzhou Juno Genomics, Inc, SCV005417109.1

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

Description

PM2_Supporting+PP3_Strong+PS4_Moderate+PP4+PS2_Moderate

#	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

Last Updated: Dec 22, 2024

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