9-132921913-C-G

Variant names:

• chr9-132921913-C-G
• rs118203402
• NM_000368.5:c.569G>C

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS1 PM1 PM2 PP3_Strong PP5_Moderate

The NM_000368.5(TSC1):​c.569G>C​(p.Arg190Pro) variant causes a missense change involving the alteration of a conserved nucleotide. 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R190H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 7.91
• Publications: 10 publications found

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]

TSC1 Gene-Disease associations (from GenCC):

• tuberous sclerosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• tuberous sclerosis 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, PanelApp Australia, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• lung 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 14 ACMG points.

• PS1: Transcript NM_000368.5 (TSC1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 30 uncertain in NM_000368.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.948
• PP5: Variant 9-132921913-C-G is Pathogenic according to our data. Variant chr9-132921913-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 49058.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.569G>C	p.Arg190Pro	missense_variant	Exon 7 of 23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.569G>C	p.Arg190Pro	missense_variant	Exon 7 of 23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.569G>C	p.Arg190Pro	missense_variant	Exon 8 of 24	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jul 06, 2016

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The R190P variant that is likely pathogenic has been identified in the TSC1 gene. Functional studiessuggest that the R190P variant results in decreased levels of TSC1 protein, reduced inhibition ofmTOR activity, and an abnormal intracellular localization pattern (Mozaffari et al., 2009). It was notobserved in approximately 6,500 individuals of European and African American ancestry in theNHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.The R190P variant is a non-conservative amino acid substitution, which is likely to impact secondaryprotein structure as these residues differ in polarity, charge, size and/or other properties. Thissubstitution occurs at a position that is conserved across species, and missense variants in a nearbyresidue (L191H, L191R) have been reported in the Human Gene Mutation Database in associationwith TSC (Stenson et al., 2014). In silico analysis predicts this variant is probably damaging to theprotein structure/function. However, the vast majority of TSC1 pathogenic variants result in proteintruncation, while missense variants have been reported only rarely (Northrup et al., 2011; Au et al.,2007). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot beexcluded.

Tuberous sclerosis syndrome Other:1

Tuberous sclerosis database (TSC1)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;.;D;.;D;.;D;.;.;.;.;.;.;.;.;.;.;D;.;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.0	.;D;D;D;.;.;.;D;D;.;D;.;.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Uncertain	2.5	M;.;M;.;M;.;M;.;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		7.9
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-6.1	D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.
Vest4		0.99
ClinPred		0.99	D
GERP RS		6.1
Varity_R		0.92
gMVP		0.94
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs118203402; hg19: chr9-135797300; COSMIC: COSV53764234; COSMIC: COSV53764234;