NM_000548.5(TSC2):c.2267G>C (p.Gly756Ala) AND Tuberous sclerosis 2

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 9, 2024
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:: RCV003513002.2

Allele description [Variation Report for NM_000548.5(TSC2):c.2267G>C (p.Gly756Ala)]

NM_000548.5(TSC2):c.2267G>C (p.Gly756Ala)

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.2267G>C (p.Gly756Ala)

HGVS:

NC_000016.10:g.2072895G>C
NG_005895.1:g.28590G>C
NM_000548.5:c.2267G>CMANE SELECT
NM_001077183.3:c.2267G>C
NM_001114382.3:c.2267G>C
NM_001318827.2:c.2156G>C
NM_001318829.2:c.2120G>C
NM_001318831.2:c.1667G>C
NM_001318832.2:c.2300G>C
NM_001363528.2:c.2267G>C
NM_001370404.1:c.2267G>C
NM_001370405.1:c.2267G>C
NM_001406663.1:c.2267G>C
NM_001406664.1:c.2267G>C
NM_001406665.1:c.2267G>C
NM_001406667.1:c.2357G>C
NM_001406668.1:c.2357G>C
NM_001406670.1:c.2156G>C
NM_001406671.1:c.2255G>C
NM_001406673.1:c.2255G>C
NM_001406675.1:c.2120G>C
NM_001406676.1:c.2120G>C
NM_001406677.1:c.2210G>C
NM_001406678.1:c.2156G>C
NM_001406679.1:c.2120G>C
NM_001406680.1:c.1667G>C
NM_001406681.1:c.1805G>C
NM_001406682.1:c.1667G>C
NM_001406683.1:c.1667G>C
NM_001406684.1:c.1667G>C
NM_001406685.1:c.1667G>C
NM_001406686.1:c.1667G>C
NM_001406687.1:c.1667G>C
NM_001406688.1:c.1667G>C
NM_001406689.1:c.923G>C
NM_001406690.1:c.923G>C
NM_001406691.1:c.923G>C
NM_001406692.1:c.923G>C
NM_001406693.1:c.923G>C
NM_001406694.1:c.923G>C
NM_001406695.1:c.923G>C
NM_001406696.1:c.923G>C
NM_001406697.1:c.923G>C
NM_001406698.1:c.665G>C
NM_021055.3:c.2267G>C
NP_000539.2:p.Gly756Ala
NP_000539.2:p.Gly756Ala
NP_001070651.1:p.Gly756Ala
NP_001107854.1:p.Gly756Ala
NP_001305756.1:p.Gly719Ala
NP_001305758.1:p.Gly707Ala
NP_001305760.1:p.Gly556Ala
NP_001305761.1:p.Gly767Ala
NP_001350457.1:p.Gly756Ala
NP_001357333.1:p.Gly756Ala
NP_001357334.1:p.Gly756Ala
NP_001393592.1:p.Gly756Ala
NP_001393593.1:p.Gly756Ala
NP_001393594.1:p.Gly756Ala
NP_001393596.1:p.Gly786Ala
NP_001393597.1:p.Gly786Ala
NP_001393599.1:p.Gly719Ala
NP_001393600.1:p.Gly752Ala
NP_001393602.1:p.Gly752Ala
NP_001393604.1:p.Gly707Ala
NP_001393605.1:p.Gly707Ala
NP_001393606.1:p.Gly737Ala
NP_001393607.1:p.Gly719Ala
NP_001393608.1:p.Gly707Ala
NP_001393609.1:p.Gly556Ala
NP_001393610.1:p.Gly602Ala
NP_001393611.1:p.Gly556Ala
NP_001393612.1:p.Gly556Ala
NP_001393613.1:p.Gly556Ala
NP_001393614.1:p.Gly556Ala
NP_001393615.1:p.Gly556Ala
NP_001393616.1:p.Gly556Ala
NP_001393617.1:p.Gly556Ala
NP_001393618.1:p.Gly308Ala
NP_001393619.1:p.Gly308Ala
NP_001393620.1:p.Gly308Ala
NP_001393621.1:p.Gly308Ala
NP_001393622.1:p.Gly308Ala
NP_001393623.1:p.Gly308Ala
NP_001393624.1:p.Gly308Ala
NP_001393625.1:p.Gly308Ala
NP_001393626.1:p.Gly308Ala
NP_001393627.1:p.Gly222Ala
NP_066399.2:p.Gly756Ala
LRG_487t1:c.2267G>C
LRG_487:g.28590G>C
LRG_487p1:p.Gly756Ala
NC_000016.9:g.2122896G>C
NM_000548.3:c.2267G>C
NR_176225.1:n.2417G>C
NR_176226.1:n.2596G>C
NR_176227.1:n.2596G>C
NR_176228.1:n.2417G>C
NR_176229.1:n.2377G>C

Protein change:

G222A

Molecular consequence:

NM_000548.5:c.2267G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001077183.3:c.2267G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001114382.3:c.2267G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001318827.2:c.2156G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001318829.2:c.2120G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001318831.2:c.1667G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001318832.2:c.2300G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001363528.2:c.2267G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001370404.1:c.2267G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001370405.1:c.2267G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406663.1:c.2267G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406664.1:c.2267G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406665.1:c.2267G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406667.1:c.2357G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406668.1:c.2357G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406670.1:c.2156G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406671.1:c.2255G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406673.1:c.2255G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406675.1:c.2120G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406676.1:c.2120G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406677.1:c.2210G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406678.1:c.2156G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406679.1:c.2120G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406680.1:c.1667G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406681.1:c.1805G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406682.1:c.1667G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406683.1:c.1667G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406684.1:c.1667G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406685.1:c.1667G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406686.1:c.1667G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406687.1:c.1667G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406688.1:c.1667G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406689.1:c.923G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406690.1:c.923G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406691.1:c.923G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406692.1:c.923G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406693.1:c.923G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406694.1:c.923G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406695.1:c.923G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406696.1:c.923G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406697.1:c.923G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406698.1:c.665G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_021055.3:c.2267G>C - missense variant - [Sequence Ontology: SO:0001583]
NR_176225.1:n.2417G>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176226.1:n.2596G>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176227.1:n.2596G>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176228.1:n.2417G>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176229.1:n.2377G>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

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

Recent activity

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cytochrome c oxidase subunit I (mitochondrion) [Protopterus dolloi]
cytochrome c oxidase subunit I (mitochondrion) [Protopterus dolloi]
gi|5835222|gnl|NCBI_MITO|COX1_10703 NP_008266.1|COX1_10703

Protein
zinc finger homeobox protein, partial [Pyxis arachnoides brygooi]
zinc finger homeobox protein, partial [Pyxis arachnoides brygooi]
gi|1959485795|gb|QQX08904.1|

Protein
cytochrome b, partial (mitochondrion) [Pyxis arachnoides brygooi]
cytochrome b, partial (mitochondrion) [Pyxis arachnoides brygooi]
gi|59783322|gb|AAX04296.1|

Protein
bone morphogenetic protein 2, partial [Pyxis arachnoides brygooi]
bone morphogenetic protein 2, partial [Pyxis arachnoides brygooi]
gi|1959480346|gb|QQX07523.1|

Protein
Jacaranda simplicifolia voucher R. Farias-Singer 1034 (ICN) tRNA-Leu gene, parti...
Jacaranda simplicifolia voucher R. Farias-Singer 1034 (ICN) tRNA-Leu gene, partial sequence; trnL-trnF intergenic spacer, complete sequence; and tRNA-Phe gene, partial sequence; chloroplast
gi|1785471181|gb|MN445298.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004262425	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 9, 2024)	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

SCV004262425

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 9, 2024)

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, SCV004262425.1

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

Description

This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 756 of the TSC2 protein (p.Gly756Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TSC2-related conditions. 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 with a negative predictive value of 95%. 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.

#	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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