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NM_000548.5(TSC2):c.5228G>A (p.Arg1743Gln) AND TSC2-related disorder

Germline classification:
Pathogenic (1 submission)
Last evaluated:
May 13, 2024
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
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:
RCV004734600.1

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]

Condition(s)

Name:
TSC2-related disorder
Synonyms:
TSC2-related condition
Identifiers:

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV005362143PreventionGenetics, part of Exact Sciences
no assertion criteria provided
Pathogenic
(May 13, 2024) 		germlineclinical testing

Help

Summary from all submissions

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

Details of each submission

From PreventionGenetics, part of Exact Sciences, SCV005362143.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The TSC2 c.5228G>A variant is predicted to result in the amino acid substitution p.Arg1743Gln. This variant (also described as p.Arg1720Gln) has been reported in multiple individuals with tuberous sclerosis (for example, see Gilbert et al. 1998. PubMed ID: 10732801; Kwiatkowski et al. 2015. PubMed ID: 25782670; Bąbol-Pokora et al. 2021. PubMed ID: 34403804; Ng et al. 2022. PubMed ID: 35918040) and has been observed to have arisen de novo in several patients (Rendtdorff et al. 2005. PubMed ID: 16114042; Qin et al. 2010. PubMed ID: 20165957; Overwater et al. 2016. PubMed ID: 27406250; Ding et al. 2020. PubMed ID: 32211034). In vitro functional studies have demonstrated that this variant leads to reduced protein expression, disrupted formation of the TSC1/TSC2 complex, and dysregulation of downstream signaling pathways (Coevoets et al. 2009. PubMed ID: 18854862; Hoogeveen-Westerveld et al. 2011. PubMed ID: 21309039; Overwater et al. 2016. PubMed ID: 27406250). This variant has not been reported in the gnomAD database and is interpreted as pathogenic by multiple submitters to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/49960/). Of note, additional missense variants affecting the same amino acid residue (p.Arg1743Trp, p.Arg1743Pro) have been reported as disease-causing in individuals with tuberous sclerosis (Jones et al. 1999. PubMed ID: 10205261; Sancak et al. 2005. PubMed ID: 15798777; Ng et al. 2022. PubMed ID: 35918040). Taken together, this variant is interpreted as pathogenic.

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

Last Updated: Dec 22, 2024