NM_000548.5(TSC2):c.2666C>T (p.Ala889Val) AND Tuberous sclerosis 2

Clinical significance:Conflicting interpretations of pathogenicity, Pathogenic(1);Uncertain significance(1) (Last evaluated: Oct 19, 2017)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000201152.1

Allele description [Variation Report for NM_000548.5(TSC2):c.2666C>T (p.Ala889Val)]

NM_000548.5(TSC2):c.2666C>T (p.Ala889Val)

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.2666C>T (p.Ala889Val)
HGVS:
  • NC_000016.10:g.2076094C>T
  • NG_005895.1:g.31789C>T
  • NM_000548.5:c.2666C>TMANE SELECT
  • NM_001077183.3:c.2666C>T
  • NM_001114382.3:c.2666C>T
  • NM_001318827.2:c.2555C>T
  • NM_001318829.2:c.2519C>T
  • NM_001318831.2:c.2066C>T
  • NM_001318832.2:c.2699C>T
  • NM_001363528.2:c.2666C>T
  • NM_001370404.1:c.2666C>T
  • NM_001370405.1:c.2666C>T
  • NM_021055.3:c.2666C>T
  • NP_000539.2:p.Ala889Val
  • NP_001070651.1:p.Ala889Val
  • NP_001107854.1:p.Ala889Val
  • NP_001305756.1:p.Ala852Val
  • NP_001305758.1:p.Ala840Val
  • NP_001305760.1:p.Ala689Val
  • NP_001305761.1:p.Ala900Val
  • NP_001350457.1:p.Ala889Val
  • NP_001357333.1:p.Ala889Val
  • NP_001357334.1:p.Ala889Val
  • NP_066399.2:p.Ala889Val
  • LRG_487t1:c.2666C>T
  • LRG_487:g.31789C>T
  • NC_000016.9:g.2126095C>T
  • NM_000548.3:c.2666C>T
  • p.(Ala889Val)
Protein change:
A689V
Links:
Tuberous sclerosis database (TSC2): TSC2_01111; dbSNP: rs137854155
NCBI 1000 Genomes Browser:
rs137854155
Molecular consequence:
  • NM_000548.5:c.2666C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001077183.3:c.2666C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001114382.3:c.2666C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001318827.2:c.2555C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001318829.2:c.2519C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001318831.2:c.2066C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001318832.2:c.2699C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001363528.2:c.2666C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001370404.1:c.2666C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001370405.1:c.2666C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_021055.3:c.2666C>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000255887Athena Diagnostics Inccriteria provided, single submitter
Pathogenic
(Jul 5, 2012)
germlineclinical testing

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

SCV000765936Invitaecriteria provided, single submitter
Uncertain significance
(Oct 19, 2017)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Summary from all submissions

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

Citations

PubMed

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

Functional assessment of TSC2 variants identified in individuals with tuberous sclerosis complex.

Hoogeveen-Westerveld M, Ekong R, Povey S, Mayer K, Lannoy N, Elmslie F, Bebin M, Dies K, Thompson C, Sparagana SP, Davies P, van Eeghen AM, Thiele EA, van den Ouweland A, Halley D, Nellist M.

Hum Mutat. 2013 Jan;34(1):167-75. doi: 10.1002/humu.22202. Epub 2012 Oct 11. Erratum in: Hum Mutat. 2013 Feb;34(2):408-10. van Eeghen, Agnies M [added]; Thiele, Elizabeth A [added].

PubMed [citation]
PMID:
22903760
See all PubMed Citations (5)

Details of each submission

From Athena Diagnostics Inc, SCV000255887.2

#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, SCV000765936.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces alanine with valine at codon 889 of the TSC2 protein (p.Ala889Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in a family with 2 members affected with Tuberous Sclerosis Complex in the Leiden Open-source Variation Database (PMID: 21309039, 21520333). ClinVar contains an entry for this variant (Variation ID: 49586). Experimental studies have shown that this missense change disrupts the protein stability and causes a higher T389/S6K ratio than the wild type TSC2, indicating inability of this variant to inhibit mTOR activity (PMID: 21309039). A different missense substitution at this codon (p.Ala889Pro) has been reported to be de novo and determined to be pathogenic (PMID: 22903760, 21520333). This suggests that the alanine residue is critical for TSC2 protein function and that other missense substitutions at this position may also be pathogenic. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

Last Updated: Nov 27, 2021

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