Submissions for variant NM_000548.5(TSC2):c.4508A>C (p.Gln1503Pro)

dbSNP: rs45516293

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000492813	SCV000581956	pathogenic	not provided	2024-11-12	criteria provided, single submitter	clinical testing	Reported previously as a heterozygous likely pathogenic variant in a patient with epilepsy; however, no further clinical or segregation information was provided (PMID: 31440721); Published functional studies demonstrate a damaging effect showing that the variant disrupts the function of the TSC1-TSC2 complex (PMID: 22903760, 21332470); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19028034, 21332470, 23389244, 11403047, 17120248, 28492532, 30255984, 17304050, 27535533, 31440721, 22903760)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000013210	SCV000644542	pathogenic	Tuberous sclerosis 2	2023-03-07	criteria provided, single submitter	clinical testing	Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TSC2 protein function. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TSC2 function (PMID: 21332470, 22903760). ClinVar contains an entry for this variant (Variation ID: 12401). This missense change has been observed in individual(s) with mild manifestations of tuberous sclerosis complex (TSC) (PMID: 11403047). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 1503 of the TSC2 protein (p.Gln1503Pro).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000043266	SCV000697470	pathogenic	Tuberous sclerosis syndrome	2017-07-28	criteria provided, single submitter	clinical testing	Variant summary: The TSC2 c.4508A>C (p.Gln1503Pro) variant involves the alteration of a conserved nucleotide that lies within the Rap GTPase activating protein domain (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 120242 control chromosomes (ExAC and publication controls). The variant was identified in two families from the same geographical area with multiple affected individuals in each family. While the physical features typical of tuberous sclerosis were mild, affected individuals had significant neuropsychiatric symptoms including pervasive developmental disorder and autism. The variant cosegregated with disease completely in 14 affected and 9 unaffected individuals (Khare_JMG_2001). A functional study revealed the variant was unable to inhibit S6K phosphorylation in cultured cells (Wentink_Clin Genet_2011). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Ambry Genetics	RCV002316192	SCV000851198	pathogenic	Hereditary cancer-predisposing syndrome	2024-05-09	criteria provided, single submitter	clinical testing	The p.Q1503P pathogenic mutation (also known as c.4508A>C), located in coding exon 34 of the TSC2 gene, results from an A to C substitution at nucleotide position 4508. The glutamine at codon 1503 is replaced by proline, an amino acid with similar properties. This pathogenic mutation was identified in two unrelated four-generation families with tuberous sclerosis complex; it co-segregated with the disease in those families (Khare L et al. J. Med. Genet., 2001 May;38:347-9).In one functional study, this alteration was found to disrupt the TSC1-TSC2 dependent inhibition of TORC1 (Wentink M et al. Clin. Genet., 2012 May;81:453-61; Hoogeveen-Westerveld M et al. Hum. Mutat., 2013 Jan;34:167-75). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.
Genome-Nilou Lab	RCV000013210	SCV002040999	likely pathogenic	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000013210	SCV003806646	likely pathogenic	Tuberous sclerosis 2	2023-01-31	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 11403047]. Functional studies indicate this variant impacts protein function [PMID: 21332470, 22903760]. This variant is expected to disrupt protein structure [internal Myriad data].
Baylor Genetics	RCV003460465	SCV004205105	pathogenic	Isolated focal cortical dysplasia type II	2023-05-02	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000043266	SCV004847791	likely pathogenic	Tuberous sclerosis syndrome	2019-12-03	criteria provided, single submitter	clinical testing	The p.Gln1503Pro variant in TSC2 has been reported in at least 2 individuals with features of tuberous sclerosis 2 syndrome (with neurodevelopmental disorder) and segregated with disease in 14 affected individuals from 2 families (Khare 2001). This variant has also been reported in ClinVar (Variation ID 12401) and was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies support an impact on protein function (Hoogeveen-Westerveld M 2013). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Tuberous sclerosis 2 syndrome. ACMG/AMP Criteria applied: PS4_Supporting, PP1_Strong, PM2, PS3_Supporting, PP3.
OMIM	RCV000013210	SCV000033457	pathogenic	Tuberous sclerosis 2	2001-05-01	no assertion criteria provided	literature only
Tuberous sclerosis database (TSC2)	RCV000043266	SCV000067068	not provided	Tuberous sclerosis syndrome		no assertion provided	curation
GeneReviews	RCV000013210	SCV000245754	not provided	Tuberous sclerosis 2		no assertion provided	literature only