rs1060503197

Positions:

• chr9-132911457-G-A
• chr9-132911457-G-C
• chr9-132911457-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 5P and 2B. PM2 PM5 PP2 BP4_Moderate

The NM_000368.5(TSC1):​c.1025C>T​(p.Pro342Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P342HK) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.91

Genes affected

TSC1 (HGNC:12362): (TSC complex subunit 1) This gene is a tumor suppressor gene that encodes the growth inhibitory protein hamartin. The encoded protein interacts with and stabilizes the GTPase activating protein tuberin. This hamartin-tuberin complex negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signaling which is a major regulator of anabolic cell growth. This protein also functions as a co-chaperone for Hsp90 that inhibits its ATPase activity. This protein functions as a facilitator of Hsp90-mediated folding of kinase and non-kinase clients, including TSC2 and thereby preventing their ubiquitination and proteasomal degradation. Mutations in this gene have been associated with tuberous sclerosis and lymphangioleiomyomatosis. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-132911456-TG-TTTGT is described in Lovd as [Likely_pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TSC1. . Gene score misZ 2.3217 (greater than the threshold 3.09). Trascript score misZ 3.6986 (greater than threshold 3.09). GenCC has associacion of gene with lung lymphangioleiomyomatosis, tuberous sclerosis 1, tuberous sclerosis, tuberous sclerosis complex, lymphangioleiomyomatosis.
• BP4: Computational evidence support a benign effect (MetaRNN=0.12728769).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC1	NM_000368.5	c.1025C>T	p.Pro342Leu	missense_variant	10/23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.1025C>T	p.Pro342Leu	missense_variant	10/23	1	NM_000368.5	ENSP00000298552	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 30, 2023

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 TSC1 protein function. ClinVar contains an entry for this variant (Variation ID: 411217). This variant has not been reported in the literature in individuals affected with TSC1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 342 of the TSC1 protein (p.Pro342Leu). -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 24, 2024

The p.P342L variant (also known as c.1025C>T), located in coding exon 8 of the TSC1 gene, results from a C to T substitution at nucleotide position 1025. The proline at codon 342 is replaced by leucine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	20
DANN	Benign	0.76
DEOGEN2	Benign	0.40	T;.;T;.;T;.;T;.;.;.;.;.;.;.;.;.;.;T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.38
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.82	.;T;T;T;.;.;.;T;T;.;T;.;.;T;T;T;T;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.13	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.3	L;.;L;.;L;.;L;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.44	N;N;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D
REVEL	Uncertain	0.33
Sift	Benign	0.66	T;T;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T
Sift4G	Benign	0.51	T;T;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T
Polyphen		0.0	B;.;B;.;B;.;B;.;.;.;.;B;B;B;.;.;.;B
Vest4		0.15
MutPred		0.60		Loss of catalytic residue at P341 (P = 0.0096);.;Loss of catalytic residue at P341 (P = 0.0096);Loss of catalytic residue at P341 (P = 0.0096);Loss of catalytic residue at P341 (P = 0.0096);Loss of catalytic residue at P341 (P = 0.0096);Loss of catalytic residue at P341 (P = 0.0096);Loss of catalytic residue at P341 (P = 0.0096);Loss of catalytic residue at P341 (P = 0.0096);.;.;Loss of catalytic residue at P341 (P = 0.0096);Loss of catalytic residue at P341 (P = 0.0096);Loss of catalytic residue at P341 (P = 0.0096);Loss of catalytic residue at P341 (P = 0.0096);Loss of catalytic residue at P341 (P = 0.0096);.;Loss of catalytic residue at P341 (P = 0.0096);
MVP		0.77
MPC		0.52
ClinPred		0.19	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.020
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1060503197; hg19: chr9-135786844;