16-2080365-C-G

Variant names:

• chr16-2080365-C-G
• rs45438205
• NM_000548.5:c.3598C>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_000548.5(TSC2):​c.3598C>G​(p.Arg1200Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1200P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.42
• Publications: 0 publications found

Genes affected

TSC2 (HGNC:12363): (TSC complex subunit 2) This gene is a tumor suppressor gene that encodes the growth inhibitory protein tuberin. Tuberin interacts with hamartin to form the TSC protein complex which functions in the control of cell growth. This TSC protein complex negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signaling which is a major regulator of anabolic cell growth. Mutations in this gene have been associated with tuberous sclerosis and lymphangioleiomyomatosis. [provided by RefSeq, May 2022]

TSC2 Gene-Disease associations (from GenCC):

• tuberous sclerosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• tuberous sclerosis 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics
• lymphangioleiomyomatosis

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• tuberous sclerosis complex

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 36 uncertain in NM_000548.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-2080365-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 49770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.928
• PP5: Variant 16-2080365-C-G is Pathogenic according to our data. Variant chr16-2080365-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2049812.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000548.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	NM_000548.5	MANE Select	c.3598C>G	p.Arg1200Gly	missense	Exon 30 of 42	NP_000539.2
	TSC2	NM_001406663.1		c.3595C>G	p.Arg1199Gly	missense	Exon 30 of 42	NP_001393592.1
	TSC2	NM_001114382.3		c.3598C>G	p.Arg1200Gly	missense	Exon 30 of 41	NP_001107854.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	ENST00000219476.9	TSL:5 MANE Select	c.3598C>G	p.Arg1200Gly	missense	Exon 30 of 42	ENSP00000219476.3
	TSC2	ENST00000350773.9	TSL:1	c.3598C>G	p.Arg1200Gly	missense	Exon 30 of 41	ENSP00000344383.4
	TSC2	ENST00000401874.7	TSL:1	c.3466C>G	p.Arg1156Gly	missense	Exon 29 of 40	ENSP00000384468.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tuberous sclerosis 2 Pathogenic:1

Dec 20, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense change has been observed in individual(s) with TSC2-related conditions (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 1200 of the TSC2 protein (p.Arg1200Gly). 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 expected to disrupt TSC2 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg1200 amino acid residue in TSC2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8824881, 9463313, 18792920, 21332470, 22867869, 25039834, 28149746). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		5.4
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.99	D
Vest4		0.96
MutPred		0.73		Loss of MoRF binding (P = 0.0449)
MVP		0.98
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.83
gMVP		0.98
Mutation Taster		=19/81	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs45438205; hg19: chr16-2130366;