Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2
The NM_000368.5(TSC1):c.1001C>T(p.Ser334Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000243 in 1,613,700 control chromosomes in the GnomAD database, including 2 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S334T) 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]
Missense variant where missense usually causes diseases, TSC1
BP4
Computational evidence support a benign effect (MetaRNN=0.015584558).
BP6
Variant 9-132911481-G-A is Benign according to our data. Variant chr9-132911481-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 41686.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132911481-G-A is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000253 (370/1461610) while in subpopulation SAS AF= 0.00247 (213/86254). AF 95% confidence interval is 0.0022. There are 2 homozygotes in gnomad4_exome. There are 240 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
Uncertain significance, no assertion criteria provided
research
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Jul 13, 2012
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Benign, criteria provided, single submitter
clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano
Oct 18, 2019
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Likely benign, criteria provided, single submitter
clinical testing
CeGaT Center for Human Genetics Tuebingen
Apr 01, 2023
TSC1: BP4, BS1 -
Likely benign, no assertion criteria provided
clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
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not specified Benign:3Other:1
Likely benign, criteria provided, single submitter
clinical testing
Genetic Services Laboratory, University of Chicago
Sep 10, 2014
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not provided, no classification provided
reference population
ITMI
Sep 19, 2013
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Benign, no assertion criteria provided
clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
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Benign, criteria provided, single submitter
clinical testing
GeneDx
Jan 31, 2018
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Tuberous sclerosis 1 Benign:3
Benign, criteria provided, single submitter
clinical testing
Genome-Nilou Lab
Nov 07, 2021
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Likely benign, criteria provided, single submitter
clinical testing
Illumina Laboratory Services, Illumina
Apr 28, 2017
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter
clinical testing
Invitae
Jan 31, 2024
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Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1854465:Tuberous sclerosis 1 Benign:2
Likely benign, criteria provided, single submitter
clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Jul 12, 2022
TSC1 NM_000368.4 exon 10 p.Ser334Leu (c.1001C>T): This variant has been reported in the literature in at least 1 individual with nonalcoholic fatty liver disease (Pelusi 2019 PMID:30842500). This variant is present in the Genome Aggregation Database (Highest reported MAF 0.01% (13/67998) (https://gnomad.broadinstitute.org/variant/9-132911481-G-A?dataset=gnomad_r3)). This variant is present in ClinVar, with several labs classifying this variant as Likely Benign or Benign (Variation ID:41686). This variant amino acid Leucine (Leu) is present in multiple species including mammals and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant suggests that this variant does not cause disease but requires further evidence. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter
clinical testing
Fulgent Genetics, Fulgent Genetics
Oct 08, 2021
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Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitter
curation
Sema4, Sema4
Dec 09, 2020
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Likely benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Apr 05, 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. -
Tuberous sclerosis syndrome Benign:1Other:1
Benign, criteria provided, single submitter
clinical testing
All of Us Research Program, National Institutes of Health
Feb 05, 2024
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not provided, no classification provided
curation
Tuberous sclerosis database (TSC1)
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Isolated focal cortical dysplasia type II Benign:1
Likely benign, criteria provided, single submitter
clinical testing
Illumina Laboratory Services, Illumina
Apr 28, 2017
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
TSC1-related disorder Benign:1
Likely benign, criteria provided, single submitter
clinical testing
PreventionGenetics, part of Exact Sciences
Mar 14, 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). -