Submissions for variant NM_000368.5(TSC1):c.1001C>T (p.Ser334Leu)

gnomAD frequency: 0.00012  dbSNP: rs118203481

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000122200	SCV000153104	likely benign	not specified	2014-09-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001080188	SCV000284662	benign	Tuberous sclerosis 1	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000398057	SCV000478245	likely benign	Isolated focal cortical dysplasia type II	2017-04-28	criteria provided, single submitter	clinical testing	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.
Illumina Laboratory Services, Illumina	RCV001080188	SCV000478246	likely benign	Tuberous sclerosis 1	2017-04-28	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV000122200	SCV000527394	benign	not specified	2018-01-31	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV000572872	SCV000675346	likely benign	Hereditary cancer-predisposing syndrome	2018-04-05	criteria provided, single submitter	clinical testing	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.
Genome-Nilou Lab	RCV001080188	SCV002040478	benign	Tuberous sclerosis 1	2021-11-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000572872	SCV002530870	likely benign	Hereditary cancer-predisposing syndrome	2020-12-09	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002490461	SCV002799201	likely benign	Lymphangiomyomatosis; Tuberous sclerosis 1; Isolated focal cortical dysplasia type II	2021-10-08	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV002490461	SCV003920597	likely benign	Lymphangiomyomatosis; Tuberous sclerosis 1; Isolated focal cortical dysplasia type II	2022-07-12	criteria provided, single submitter	clinical testing	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.
CeGaT Center for Human Genetics Tuebingen	RCV000034598	SCV004156654	likely benign	not provided	2023-04-01	criteria provided, single submitter	clinical testing	TSC1: BP4, BS1
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000034598	SCV004221379	benign	not provided	2019-10-18	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000054847	SCV004840501	benign	Tuberous sclerosis syndrome	2024-02-05	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000034598	SCV005225986	likely benign	not provided		criteria provided, single submitter	not provided
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034598	SCV000043518	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
Tuberous sclerosis database (TSC1)	RCV000054847	SCV000065752	not provided	Tuberous sclerosis syndrome		no assertion provided	curation
ITMI	RCV000122200	SCV000086419	not provided	not specified	2013-09-19	no assertion provided	reference population
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000034598	SCV001741806	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000122200	SCV001966265	benign	not specified		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003944882	SCV004775245	likely benign	TSC1-related disorder	2019-03-14	no assertion criteria provided	clinical testing	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).