9-132912446-A-G

Variant names:

• chr9-132912446-A-G
• rs118203447
• NM_000368.5:c.749T>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000368.5(TSC1):​c.749T>C​(p.Leu250Ser) 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 Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 5.73

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.884

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.749T>C	p.Leu250Ser	missense_variant	Exon 9 of 23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.749T>C	p.Leu250Ser	missense_variant	Exon 9 of 23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.749T>C	p.Leu250Ser	missense_variant	Exon 10 of 24	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis syndrome Uncertain:1

Apr 16, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces leucine with serine at codon 250 of the TSC1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with TSC1-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Tuberous sclerosis 1 Uncertain:1

Nov 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 250 of the TSC1 protein (p.Leu250Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TSC1-related conditions. ClinVar contains an entry for this variant (Variation ID: 466154). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TSC1 protein function. 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Dec 19, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L250S variant (also known as c.749T>C), located in coding exon 7 of the TSC1 gene, results from a T to C substitution at nucleotide position 749. The leucine at codon 250 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;.;D;.;D;.;D;.;.;.;.;.;.;.;.;.;.;D;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	.;D;T;D;.;.;.;D;T;.;D;.;.;D;D;D;D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Uncertain	2.3	M;.;M;.;M;.;M;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.1	D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0030	D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.
Sift4G	Uncertain	0.018	D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.
Polyphen		0.77	P;.;P;.;P;.;P;.;.;.;.;D;D;D;.;.;.;D;.
Vest4		0.72
MutPred		0.77		Loss of stability (P = 0.0055);.;Loss of stability (P = 0.0055);Loss of stability (P = 0.0055);Loss of stability (P = 0.0055);Loss of stability (P = 0.0055);Loss of stability (P = 0.0055);Loss of stability (P = 0.0055);Loss of stability (P = 0.0055);.;.;Loss of stability (P = 0.0055);Loss of stability (P = 0.0055);Loss of stability (P = 0.0055);Loss of stability (P = 0.0055);Loss of stability (P = 0.0055);.;Loss of stability (P = 0.0055);.;
MVP		0.86
MPC		1.7
ClinPred		0.98	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.55

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

Publications

LitVar

Other links and lift over

dbSNP: rs118203447; hg19: chr9-135787833;