Submissions for variant NM_000548.5(TSC2):c.1622C>G (p.Pro541Arg)

gnomAD frequency: 0.00001  dbSNP: rs752953762

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000298128	SCV000395587	uncertain significance	Tuberous sclerosis syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000461333	SCV000544495	benign	Tuberous sclerosis 2	2023-09-10	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765263	SCV000896516	uncertain significance	Lymphangiomyomatosis; Isolated focal cortical dysplasia type II; Tuberous sclerosis 2	2018-10-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001012444	SCV001172895	likely benign	Hereditary cancer-predisposing syndrome	2023-12-06	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	RCV000461333	SCV002039563	uncertain significance	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV003482249	SCV004229358	uncertain significance	not provided	2023-08-22	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). Computational tools predict that this variant is not damaging.
All of Us Research Program, National Institutes of Health	RCV000298128	SCV004833098	uncertain significance	Tuberous sclerosis syndrome	2023-05-04	criteria provided, single submitter	clinical testing	This missense variant replaces proline with arginine at codon 541 of the TSC2 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 TSC2-related disorders in the literature. This variant has been identified in 1/250182 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.