Submissions for variant NM_000368.5(TSC1):c.3130G>A (p.Glu1044Lys)

gnomAD frequency: 0.00001  dbSNP: rs796053462

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000189860	SCV000243513	uncertain significance	not provided	2012-08-07	criteria provided, single submitter	clinical testing	p.Glu1044Lys (GAG>AAG):c.3130 G>A in exon 23 of the TSC1 gene (NM_000368.3). The Glu1044Lys missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Project has not identified Glu1044Lys in approximately 6,500 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. The amino acid substitution is non-conservative, as a negatively charged Glutamic acid residue is replaced by a positively charged Lysine residue. However, it alters a position in the protein that is not conserved, and multiple in silico algorithms predict Glu1044Lys is likely not pathogenic. Additionally, the vast majority of TSC1 mutations result in protein truncation, while missense mutations have been reported only rarely (Northrup et al., 2011; Au et al., 2007). Therefore, based on the currently available information, it is unclear whether Glu1044Lys is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001079866	SCV001003157	benign	Tuberous sclerosis 1	2024-01-28	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001079866	SCV002040011	likely benign	Tuberous sclerosis 1	2021-11-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV002256098	SCV002531425	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-07	criteria provided, single submitter	curation
Ambry Genetics	RCV002256098	SCV002607442	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-15	criteria provided, single submitter	clinical testing	The p.E1044K variant (also known as c.3130G>A), located in coding exon 21 of the TSC1 gene, results from a G to A substitution at nucleotide position 3130. The glutamic acid at codon 1044 is replaced by lysine, an amino acid with similar properties. This variant was detected in a 65-year-old male with a personal history of leiomyosarcoma, melanoma, papillary renal cell cancer, prostate cancer and testicular cancer who underwent germline testing using an 18-gene cancer panel (Herman M et al. Clin Genitourin Cancer, 2016 Apr;14:e221-3). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001079866	SCV002767617	uncertain significance	Tuberous sclerosis 1	2020-05-25	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as VOUS. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0502 - Missense variant with conflicting in-silico predictions and/or uninformative conservation. (N) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0807 - Variant has not previously been reported in a clinical context. (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N)
All of Us Research Program, National Institutes of Health	RCV003996858	SCV004830868	uncertain significance	Tuberous sclerosis syndrome	2023-06-26	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 1044 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 not been identified 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.