NM_000548.5(TSC2):c.5345C>T (p.Ala1782Val) AND Tuberous sclerosis 2

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jun 22, 2022
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:: RCV002900008.3

Allele description [Variation Report for NM_000548.5(TSC2):c.5345C>T (p.Ala1782Val)]

NM_000548.5(TSC2):c.5345C>T (p.Ala1782Val)

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.5345C>T (p.Ala1782Val)

HGVS:

NC_000016.10:g.2088531C>T
NG_005895.1:g.44226C>T
NG_008617.1:g.54690G>A
NM_000548.5:c.5345C>TMANE SELECT
NM_001077183.3:c.5144C>T
NM_001114382.3:c.5276C>T
NM_001318827.2:c.5036C>T
NM_001318829.2:c.5000C>T
NM_001318831.2:c.4613C>T
NM_001318832.2:c.5177C>T
NM_001363528.2:c.5147C>T
NM_001370404.1:c.5213C>T
NM_001370405.1:c.5204C>T
NM_001406663.1:c.5342C>T
NM_001406664.1:c.5273C>T
NM_001406665.1:c.5267C>T
NM_001406667.1:c.5237C>T
NM_001406668.1:c.5234C>T
NM_001406670.1:c.5165C>T
NM_001406671.1:c.5135C>T
NM_001406673.1:c.5132C>T
NM_001406675.1:c.5129C>T
NM_001406676.1:c.5126C>T
NM_001406677.1:c.5087C>T
NM_001406678.1:c.5033C>T
NM_001406679.1:c.4997C>T
NM_001406680.1:c.4745C>T
NM_001406681.1:c.4685C>T
NM_001406682.1:c.4676C>T
NM_001406683.1:c.4676C>T
NM_001406684.1:c.4673C>T
NM_001406685.1:c.4547C>T
NM_001406686.1:c.4547C>T
NM_001406687.1:c.4544C>T
NM_001406688.1:c.4544C>T
NM_001406689.1:c.3932C>T
NM_001406690.1:c.3872C>T
NM_001406691.1:c.3869C>T
NM_001406692.1:c.3803C>T
NM_001406693.1:c.3803C>T
NM_001406694.1:c.3803C>T
NM_001406695.1:c.3800C>T
NM_001406696.1:c.3800C>T
NM_001406697.1:c.3800C>T
NM_001406698.1:c.3542C>T
NM_021055.3:c.5216C>T
NP_000539.2:p.Ala1782Val
NP_000539.2:p.Ala1782Val
NP_001070651.1:p.Ala1715Val
NP_001107854.1:p.Ala1759Val
NP_001305756.1:p.Ala1679Val
NP_001305758.1:p.Ala1667Val
NP_001305760.1:p.Ala1538Val
NP_001305761.1:p.Ala1726Val
NP_001350457.1:p.Ala1716Val
NP_001357333.1:p.Ala1738Val
NP_001357334.1:p.Ala1735Val
NP_001393592.1:p.Ala1781Val
NP_001393593.1:p.Ala1758Val
NP_001393594.1:p.Ala1756Val
NP_001393596.1:p.Ala1746Val
NP_001393597.1:p.Ala1745Val
NP_001393599.1:p.Ala1722Val
NP_001393600.1:p.Ala1712Val
NP_001393602.1:p.Ala1711Val
NP_001393604.1:p.Ala1710Val
NP_001393605.1:p.Ala1709Val
NP_001393606.1:p.Ala1696Val
NP_001393607.1:p.Ala1678Val
NP_001393608.1:p.Ala1666Val
NP_001393609.1:p.Ala1582Val
NP_001393610.1:p.Ala1562Val
NP_001393611.1:p.Ala1559Val
NP_001393612.1:p.Ala1559Val
NP_001393613.1:p.Ala1558Val
NP_001393614.1:p.Ala1516Val
NP_001393615.1:p.Ala1516Val
NP_001393616.1:p.Ala1515Val
NP_001393617.1:p.Ala1515Val
NP_001393618.1:p.Ala1311Val
NP_001393619.1:p.Ala1291Val
NP_001393620.1:p.Ala1290Val
NP_001393621.1:p.Ala1268Val
NP_001393622.1:p.Ala1268Val
NP_001393623.1:p.Ala1268Val
NP_001393624.1:p.Ala1267Val
NP_001393625.1:p.Ala1267Val
NP_001393626.1:p.Ala1267Val
NP_001393627.1:p.Ala1181Val
NP_066399.2:p.Ala1739Val
LRG_487t1:c.5345C>T
LRG_487:g.44226C>T
LRG_487p1:p.Ala1782Val
NC_000016.9:g.2138532C>T
NM_000548.3:c.5345C>T
NR_176225.1:n.5297C>T
NR_176226.1:n.5545C>T
NR_176227.1:n.5473C>T
NR_176228.1:n.5294C>T
NR_176229.1:n.5219C>T

Protein change:

A1181V

Molecular consequence:

NM_000548.5:c.5345C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001077183.3:c.5144C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001114382.3:c.5276C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001318827.2:c.5036C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001318829.2:c.5000C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001318831.2:c.4613C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001318832.2:c.5177C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001363528.2:c.5147C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001370404.1:c.5213C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001370405.1:c.5204C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406663.1:c.5342C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406664.1:c.5273C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406665.1:c.5267C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406667.1:c.5237C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406668.1:c.5234C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406670.1:c.5165C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406671.1:c.5135C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406673.1:c.5132C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406675.1:c.5129C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406676.1:c.5126C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406677.1:c.5087C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406678.1:c.5033C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406679.1:c.4997C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406680.1:c.4745C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406681.1:c.4685C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406682.1:c.4676C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406683.1:c.4676C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406684.1:c.4673C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406685.1:c.4547C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406686.1:c.4547C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406687.1:c.4544C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406688.1:c.4544C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406689.1:c.3932C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406690.1:c.3872C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406691.1:c.3869C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406692.1:c.3803C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406693.1:c.3803C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406694.1:c.3803C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406695.1:c.3800C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406696.1:c.3800C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406697.1:c.3800C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406698.1:c.3542C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_021055.3:c.5216C>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
SCV003246231	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jun 22, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003246231

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jun 22, 2022)

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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, SCV003246231.2

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

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. 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. This variant has not been reported in the literature in individuals affected with TSC2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1782 of the TSC2 protein (p.Ala1782Val).

#	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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