Submissions for variant NM_000368.5(TSC1):c.3076G>A (p.Ala1026Thr)

dbSNP: rs533565295

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000424313	SCV000515616	likely benign	not specified	2015-12-11	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000556341	SCV000641619	benign	Tuberous sclerosis 1	2024-11-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001018495	SCV001179742	likely benign	Hereditary cancer-predisposing syndrome	2018-02-28	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	RCV000556341	SCV002040345	benign	Tuberous sclerosis 1	2021-11-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV001018495	SCV002531418	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-07	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV003996015	SCV004840248	uncertain significance	Tuberous sclerosis syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 1026 of the TSC1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with TSC1-related disorders in the literature. This variant has been identified in 3/249426 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
PreventionGenetics, part of Exact Sciences	RCV004745375	SCV005346475	uncertain significance	TSC1-related disorder	2024-06-16	no assertion criteria provided	clinical testing	The TSC1 c.3076G>A variant is predicted to result in the amino acid substitution p.Ala1026Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0065% of alleles in individuals of South Asian descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/379061/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.