Submissions for variant NM_000368.5(TSC1):c.1079C>A (p.Thr360Asn)

gnomAD frequency: 0.00033  dbSNP: rs118203493

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163322	SCV000213850	likely benign	Hereditary cancer-predisposing syndrome	2018-10-10	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.
PreventionGenetics, part of Exact Sciences	RCV000122185	SCV000303840	likely benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001083517	SCV000478241	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.
Illumina Laboratory Services, Illumina	RCV000404533	SCV000478242	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.
GeneDx	RCV000122185	SCV000514991	benign	not specified	2018-01-10	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.
Invitae	RCV001083517	SCV000562509	benign	Tuberous sclerosis 1	2024-01-31	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000122185	SCV000860720	benign	not specified	2018-04-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000122185	SCV001362454	benign	not specified	2019-12-23	criteria provided, single submitter	clinical testing	Variant summary: TSC1 c.1079C>A (p.Thr360Asn) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00076 in 251326 control chromosomes in the gnomAD database, including 4 homozygotes. The observed variant frequency is approximately 30 fold of the estimated maximal expected allele frequency for a pathogenic variant in TSC1 causing Tuberous Sclerosis Complex phenotype (2.5e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1079C>A in individuals affected with Tuberous Sclerosis Complex and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (n=3)/likely benign(n=2). Based on the evidence outlined above, the variant was classified as benign.
Genome-Nilou Lab	RCV001083517	SCV002040468	benign	Tuberous sclerosis 1	2021-11-07	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002504867	SCV002804596	likely benign	Lymphangiomyomatosis; Tuberous sclerosis 1; Isolated focal cortical dysplasia type II	2022-04-17	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000034599	SCV003917727	benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	TSC1: BS1, BS2
Myriad Genetics, Inc.	RCV001083517	SCV004018704	benign	Tuberous sclerosis 1	2023-07-06	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic.
All of Us Research Program, National Institutes of Health	RCV000054852	SCV004840489	likely benign	Tuberous sclerosis syndrome	2024-02-05	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034599	SCV000043517	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
Tuberous sclerosis database (TSC1)	RCV000054852	SCV000065765	not provided	Tuberous sclerosis syndrome		no assertion provided	curation
Tuberous sclerosis database (TSC1)	RCV000054950	SCV000083166	not provided	Autism spectrum disorder		no assertion provided	curation
ITMI	RCV000122185	SCV000086402	not provided	not specified	2013-09-19	no assertion provided	reference population