NM_000548.5(TSC2):c.3095G>C (p.Arg1032Pro) AND Tuberous sclerosis 2

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Jul 10, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000201071.4

Allele description [Variation Report for NM_000548.5(TSC2):c.3095G>C (p.Arg1032Pro)]

NM_000548.5(TSC2):c.3095G>C (p.Arg1032Pro)

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.3095G>C (p.Arg1032Pro)
HGVS:
  • NC_000016.10:g.2079160G>C
  • NG_005895.1:g.34855G>C
  • NM_000548.5:c.3095G>CMANE SELECT
  • NM_001077183.3:c.2963G>C
  • NM_001114382.3:c.3095G>C
  • NM_001318827.2:c.2855G>C
  • NM_001318829.2:c.2819G>C
  • NM_001318831.2:c.2363G>C
  • NM_001318832.2:c.2996G>C
  • NM_001363528.2:c.2966G>C
  • NM_001370404.1:c.2963G>C
  • NM_001370405.1:c.2966G>C
  • NM_021055.3:c.2966G>C
  • NP_000539.2:p.Arg1032Pro
  • NP_001070651.1:p.Arg988Pro
  • NP_001107854.1:p.Arg1032Pro
  • NP_001305756.1:p.Arg952Pro
  • NP_001305758.1:p.Arg940Pro
  • NP_001305760.1:p.Arg788Pro
  • NP_001305761.1:p.Arg999Pro
  • NP_001350457.1:p.Arg989Pro
  • NP_001357333.1:p.Arg988Pro
  • NP_001357334.1:p.Arg989Pro
  • NP_066399.2:p.Arg989Pro
  • LRG_487t1:c.3095G>C
  • LRG_487:g.34855G>C
  • NC_000016.9:g.2129161G>C
  • NM_000548.3:c.3095G>C
  • p.(Arg1032Pro)
Protein change:
R1032P
Links:
Tuberous sclerosis database (TSC2): TSC2_00739; dbSNP: rs45491698
NCBI 1000 Genomes Browser:
rs45491698
Molecular consequence:
  • NM_000548.5:c.3095G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001077183.3:c.2963G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001114382.3:c.3095G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001318827.2:c.2855G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001318829.2:c.2819G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001318831.2:c.2363G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001318832.2:c.2996G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001363528.2:c.2966G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001370404.1:c.2963G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001370405.1:c.2966G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_021055.3:c.2966G>C - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Tuberous sclerosis 2 (TSC2)
Identifiers:
MONDO: MONDO:0013199; MedGen: C1860707; Orphanet: 805; OMIM: 613254

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000255889Athena Diagnostics Inccriteria provided, single submitter
Likely pathogenic
(Jul 9, 2015)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV000644403Invitaecriteria provided, single submitter
Pathogenic
(May 3, 2017)
germlineclinical testing

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

SCV001423569Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute,Kanazawa Medical Universitycriteria provided, single submitter
Likely pathogenic
(Jul 10, 2020)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
Japanesegermlineyes1not providednot providednot providednot providedclinical testing

Citations

PubMed

Functional assessment of variants in the TSC1 and TSC2 genes identified in individuals with Tuberous Sclerosis Complex.

Hoogeveen-Westerveld M, Wentink M, van den Heuvel D, Mozaffari M, Ekong R, Povey S, den Dunnen JT, Metcalfe K, Vallee S, Krueger S, Bergoffen J, Shashi V, Elmslie F, Kwiatkowski D, Sampson J, Vidales C, Dzarir J, Garcia-Planells J, Dies K, Maat-Kievit A, van den Ouweland A, Halley D, et al.

Hum Mutat. 2011 Apr;32(4):424-35. doi: 10.1002/humu.21451. Epub 2011 Mar 8.

PubMed [citation]
PMID:
21309039

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 (4)

Details of each submission

From Athena Diagnostics Inc, SCV000255889.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000644403.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

This sequence change replaces arginine with proline at codon 1032 of the TSC2 protein (p.Arg1032Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been reported in multiple individuals in the TSC2 Leiden Open-source Variation Database, and has been shown to arise de novo in two individuals affected with tuberous sclerosis complex (TSC) (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 49241). An experimental study has shown that this missense change impacts the TSC1-TSC2 complex function and prevents TSC complex-dependent inhibition of mTOR activity (PMID: 21309039). For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute,Kanazawa Medical University, SCV001423569.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1Japanese1not providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided1not providednot providednot provided

Last Updated: Oct 30, 2021

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