Submissions for variant NM_000368.5(TSC1):c.3184C>T (p.Arg1062Trp)

gnomAD frequency: 0.00018  dbSNP: rs118203745

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001093203	SCV000243479	benign	not provided	2020-06-23	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 21309039, 20165957)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000227692	SCV000284718	benign	Tuberous sclerosis 1	2024-01-25	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000227692	SCV000296908	uncertain significance	Tuberous sclerosis 1	2015-08-24	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000189827	SCV000540598	uncertain significance	not specified	2016-06-16	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ClinVar: 1 LB; Reported in one proband, functional studies do not support pathogenicity
Ambry Genetics	RCV000563572	SCV000675353	likely benign	Hereditary cancer-predisposing syndrome	2019-02-22	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.
Mendelics	RCV000227692	SCV001137927	benign	Tuberous sclerosis 1	2019-05-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000189827	SCV001160281	uncertain significance	not specified	2019-03-04	criteria provided, single submitter	clinical testing	The TSC1 c.3184C>T; p.Arg1062Trp variant (rs118203745) is reported in the literature in an individual with tuberous sclerosis (Qin 2010). However, functional assays demonstrate the variant protein behaves similarly to wild type protein (Hoogeveen-Westerveld 2011). This variant is reported with conflicting interpretations in ClinVar (Variation ID: 49015). It is found in the general population with an overall allele frequency of 0.02% (44/282762 alleles) in the Genome Aggregation Database. The arginine at codon 1062 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant may be deleterious. However, due to limited information, the clinical significance of this variant is uncertain at this time. References: Hoogeveen-Westerveld M et al. Functional assessment of variants in the TSC1 and TSC2 genes identified in individuals with Tuberous Sclerosis Complex. Hum Mutat. 2011 Apr;32(4):424-35. Qin W et al. Ultra deep sequencing detects a low rate of mosaic mutations in tuberous sclerosis complex. Hum Genet. 2010 Mar;127(5):573-82.
Illumina Laboratory Services, Illumina	RCV001167647	SCV001330167	benign	Isolated focal cortical dysplasia type II	2017-04-27	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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV000227692	SCV001330168	likely benign	Tuberous sclerosis 1	2017-04-27	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.
Genome-Nilou Lab	RCV000227692	SCV002040008	likely benign	Tuberous sclerosis 1	2021-11-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000563572	SCV002531433	benign	Hereditary cancer-predisposing syndrome	2020-12-13	criteria provided, single submitter	curation
Tuberous sclerosis database (TSC1)	RCV000042266	SCV000066055	not provided	Tuberous sclerosis syndrome		no assertion provided	curation
PreventionGenetics, part of Exact Sciences	RCV003915005	SCV004729125	likely benign	TSC1-related disorder	2023-03-28	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).