Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM1PP2BP4BP6BS2
The NM_000368.5(TSC1):c.532G>A(p.Val178Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000165 in 1,613,958 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign 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. V178F) has been classified as Uncertain significance.
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]
Verdict is Likely_benign. Variant got -3 ACMG points.
PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 15 uncertain in NM_000368.5
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=0.2971514).
BP6
Variant 9-132921950-C-T is Benign according to our data. Variant chr9-132921950-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 49053.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, not_provided=2, Uncertain_significance=3, Likely_benign=4}. Variant chr9-132921950-C-T is described in Lovd as [Benign].
This variant is associated with the following publications: (PMID: 10363127, 9863590, 24728327, 30842500) -
Uncertain significance, criteria provided, single submitter
clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Nov 03, 2021
- -
Uncertain significance, criteria provided, single submitter
clinical testing
Eurofins Ntd Llc (ga)
Jun 30, 2015
- -
Likely benign, no assertion criteria provided
clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center
-
- -
Likely benign, no assertion criteria provided
clinical testing
Clinical Genetics, Academic Medical Center
-
- -
Likely benign, criteria provided, single submitter
clinical testing
CeGaT Center for Human Genetics Tuebingen
Jul 01, 2024
TSC1: BP5 -
Tuberous sclerosis 1 Uncertain:1Benign:3
Benign, criteria provided, single submitter
clinical testing
Genome-Nilou Lab
Nov 07, 2021
- -
Likely benign, criteria provided, single submitter
clinical testing
Illumina Laboratory Services, Illumina
Jan 12, 2018
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter
clinical testing
Invitae
Jan 31, 2024
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Uncertain significance, criteria provided, single submitter
clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Feb 27, 2018
PP3 -
Hereditary cancer-predisposing syndrome Benign:2
Benign, criteria provided, single submitter
curation
Sema4, Sema4
Nov 18, 2020
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Likely benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Apr 27, 2018
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Isolated focal cortical dysplasia type II Benign:1
Benign, criteria provided, single submitter
clinical testing
Illumina Laboratory Services, Illumina
Jan 12, 2018
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
TSC1-related disorder Benign:1
Likely benign, criteria provided, single submitter
clinical testing
PreventionGenetics, part of Exact Sciences
Apr 23, 2019
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -