16-2062995-G-A

Variant names:

• chr16-2062995-G-A
• rs45494392
• NM_000548.5:c.1385G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000548.5(TSC2):​c.1385G>A​(p.Arg462His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000214 in 1,398,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R462P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:5 O:1
• Conservation: PhyloP100: 9.16
• Publications: 7 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 11 benign, 27 uncertain in NM_000548.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.935

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.1385G>A	p.Arg462His	missense_variant	Exon 14 of 42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.1385G>A	p.Arg462His	missense_variant	Exon 14 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000214 AC: 3 AN: 1398856 Hom.: 0 Cov.: 31 AF XY: 0.00000290 AC XY: 2 AN XY: 689972

African (AFR) AF: 0.00 AC: 0 AN: 31590

American (AMR) AF: 0.00 AC: 0 AN: 35702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25172

East Asian (EAS) AF: 0.00 AC: 0 AN: 35732

South Asian (SAS) AF: 0.00 AC: 0 AN: 79232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48998

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5602

European-Non Finnish (NFE) AF: 0.00000278 AC: 3 AN: 1078852

Other (OTH) AF: 0.00 AC: 0 AN: 57976

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000295 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:5 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Tuberous sclerosis 2 Uncertain:2

Nov 07, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 462 of the TSC2 protein (p.Arg462His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with tuberous sclerosis complex (PMID: 21520333, 37432431). ClinVar contains an entry for this variant (Variation ID: 50193). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt TSC2 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects TSC2 function (PMID: 21309039). 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. -

not provided Uncertain:2

Jul 07, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Functional assays demonstrate that the R462H variant results in an unstable protein; detailed clinical information is unavailable (PMID: 21309039); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32498851, 37432431, 34513752, 21309039, 39726432, 38806662) -

Oct 01, 2021

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Feb 07, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R462H variant (also known as c.1385G>A), located in coding exon 13 of the TSC2 gene, results from a G to A substitution at nucleotide position 1385. The arginine at codon 462 is replaced by histidine, an amino acid with highly similar properties. This variant has been reported in multiple individuals with features consistent with infantile TSC2-related cardiac rhabdomyomas (Ambry internal data; Qi Y et al. Front Pediatr. 2021 Aug;9:628238; Milon V et al. Eur J Hum Genet. 2024 Dec;32(12):1590-1598; Capal JK et al. Ann Child Neurol Soc. 2024 Jun;2(2):106-119), however, in some cases, additional family members who were identified as carriers reported no clinical features of Tuberous sclerosis complex (Qi Y et al. Front Pediatr. 2021 Aug;9:628238; Milon V et al. Eur J Hum Genet. 2024 Dec;32(12):1590-1598). A functional analysis of this alteration using a transfection-based immunoblot assay indicated this alteration to have phosphorylation higher than wild-type TSC2 and reduced TSC1 binding and stabilization (Hoogeveen-Westerveld M et al. Hum Mutat. 2011 Apr;32:424-35). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Isolated focal cortical dysplasia type II Uncertain:1

Nov 02, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tuberous sclerosis syndrome Other:1

-

Tuberous sclerosis database (TSC2)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D;.;.;.;.;.;.;.;.;.;.;.;D;.;D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Uncertain	2.7	M;.;.;.;M;M;.;.;.;M;.;M;.;.;.
PhyloP100		9.2
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-4.3	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Sift4G	Uncertain	0.0070	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Polyphen		0.99	D;.;.;.;D;D;.;.;D;D;.;.;.;.;.
Vest4		0.98
MutPred		0.74		Loss of MoRF binding (P = 0.0141);Loss of MoRF binding (P = 0.0141);Loss of MoRF binding (P = 0.0141);.;Loss of MoRF binding (P = 0.0141);Loss of MoRF binding (P = 0.0141);Loss of MoRF binding (P = 0.0141);Loss of MoRF binding (P = 0.0141);.;Loss of MoRF binding (P = 0.0141);Loss of MoRF binding (P = 0.0141);Loss of MoRF binding (P = 0.0141);Loss of MoRF binding (P = 0.0141);Loss of MoRF binding (P = 0.0141);.;
MVP		0.96
ClinPred		0.99	D
GERP RS		5.2
PromoterAI		-0.013	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.64
gMVP		0.86
Mutation Taster		=37/63	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.010		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: rs45494392; hg19: chr16-2112996; COSMIC: COSV54783764;