NM_000548.5(TSC2):c.1819G>T (p.Ala607Ser) AND Tuberous sclerosis 2

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Mar 6, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV002513720.3

Allele description [Variation Report for NM_000548.5(TSC2):c.1819G>T (p.Ala607Ser)]

NM_000548.5(TSC2):c.1819G>T (p.Ala607Ser)

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.1819G>T (p.Ala607Ser)

HGVS:

NC_000016.10:g.2070558G>T
NG_005895.1:g.26253G>T
NM_000548.5:c.1819G>TMANE SELECT
NM_001077183.3:c.1819G>T
NM_001114382.3:c.1819G>T
NM_001318827.2:c.1708G>T
NM_001318829.2:c.1672G>T
NM_001318831.2:c.1219G>T
NM_001318832.2:c.1852G>T
NM_001363528.2:c.1819G>T
NM_001370404.1:c.1819G>T
NM_001370405.1:c.1819G>T
NM_021055.3:c.1819G>T
NP_000539.2:p.Ala607Ser
NP_001070651.1:p.Ala607Ser
NP_001107854.1:p.Ala607Ser
NP_001305756.1:p.Ala570Ser
NP_001305758.1:p.Ala558Ser
NP_001305760.1:p.Ala407Ser
NP_001305761.1:p.Ala618Ser
NP_001350457.1:p.Ala607Ser
NP_001357333.1:p.Ala607Ser
NP_001357334.1:p.Ala607Ser
NP_066399.2:p.Ala607Ser
LRG_487t1:c.1819G>T
LRG_487:g.26253G>T
NC_000016.9:g.2120559G>T
NM_000548.3:c.1819G>T
p.(Ala607Ser)

Protein change:

A407S

Links:

Tuberous sclerosis database (TSC2): TSC2_02019; dbSNP: rs45517203

NCBI 1000 Genomes Browser:

rs45517203

Molecular consequence:

NM_000548.5:c.1819G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001077183.3:c.1819G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001114382.3:c.1819G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001318827.2:c.1708G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001318829.2:c.1672G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001318831.2:c.1219G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001318832.2:c.1852G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001363528.2:c.1819G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001370404.1:c.1819G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001370405.1:c.1819G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_021055.3:c.1819G>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003511260	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Mar 6, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 21309039, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003511260

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Mar 6, 2023)

germline

clinical testing

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

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

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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003511260.2

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

Description

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. Experimental studies have shown that this missense change does not substantially affect TSC2 function (PMID: 21309039). 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) performed at Invitae indicates that this missense variant is not expected to disrupt TSC2 protein function. ClinVar contains an entry for this variant (Variation ID: 65184). This missense change has been observed in individual(s) with clinical features of tuberous sclerosis complex (PMID: 21309039). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 607 of the TSC2 protein (p.Ala607Ser).

#	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

Last Updated: Sep 29, 2024

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