Submissions for variant NM_000548.5(TSC2):c.5138G>A (p.Arg1713His)

gnomAD frequency: 0.00001  dbSNP: rs45517395

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129852	SCV000184669	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-20	criteria provided, single submitter	clinical testing	The p.R1713H pathogenic mutation (also known as c.5138G>A), located in coding exon 39 of the TSC2 gene, results from a G to A substitution at nucleotide position 5138. The arginine at codon 1713 is replaced by histidine, an amino acid with highly similar properties. This mutation has been reported in multiple individuals meeting clinical diagnostic criteria for tuberous sclerosis complex (TSC), including an individual with infantile-onset TSC and 2 unrelated children with classic TSC phenotypes and positive family histories (Hirfanoglu T and Gupta A Pediatr. Neurol. 2010; 42:343-7; Niemi AK et al. Am. J. Med. Genet. A 2011; 155A:2534-7). Interestingly, both individuals described by Niemi and colleagues presented with horseshoe kidney, a rarely-observed finding in TSC patients. Functional analyses of this alteration demonstrated significant associated reductions in both TSC2 stability and TSC1 protein levels compared to wild-type (Hoogeveen-Westerveld M et al. Hum. Mutat. 2011; 32:424-35). In addition, this mutation was reported in one patient with a diagnosis of hemimegalencephaly (D'Gama AM et al. Ann. Neurol., 2015 Apr;77:720-5). Another alteration at the same codon, p.R1713P, has been reported as a pathogenic de novo mutation in an individual with sporadic TSC (Leiden Open Variation Database (LOVD) [available from http://chromium.liacs.nl/LOVD2/TSC/home.php?select_db=TSC2]). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000254730	SCV000322137	pathogenic	not provided	2023-08-29	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect, as the variant results in an unstable protein that has a destabilizing effect on the TSC1/TSC2 protein complex (Hoogeveen-Westerveld et al., 2011); 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: 28152038, 20399389, 21910228, 29281825, 25599672, 25432535, 28127866, 29655203, 33011641, 33623416, 18466115, 30787465, 21309039, 35163267, 35429229)
Invitae	RCV000459221	SCV000544312	pathogenic	Tuberous sclerosis 2	2023-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1713 of the TSC2 protein (p.Arg1713His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with tuberous sclerosis complex, hemimegalencephaly, and atypical presentation of tuberous sclerosis complex (PMID: 20399389, 21910228, 25599672, 28127866). It has also been observed to segregate with disease in related individuals. This variant is also known as R1690H. ClinVar contains an entry for this variant (Variation ID: 49930). 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. Experimental studies have shown that this missense change affects TSC2 function (PMID: 21309039). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763367	SCV000894063	pathogenic	Lymphangiomyomatosis; Isolated focal cortical dysplasia type II; Tuberous sclerosis 2	2018-10-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000254730	SCV001248124	pathogenic	not provided	2017-08-01	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000254730	SCV001880090	pathogenic	not provided	2021-02-22	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). In some published literature, this variant is referred to as R1690H. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. This variant appears to segregate with disease in at least one family. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant caused loss of inhibition of downstream signaling (PMID: 21309039). Computational tools predict that this variant is damaging.
Genome-Nilou Lab	RCV000459221	SCV002041017	pathogenic	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000459221	SCV004189835	likely pathogenic	Tuberous sclerosis 2	2023-09-05	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: 28127866, 25599672, 21910228, 20399389]. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 21309039].
Color Diagnostics, LLC DBA Color Health	RCV000459221	SCV004360939	likely pathogenic	Tuberous sclerosis 2	2023-04-27	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 1713 of the TSC2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies with this variant have demonstrated that phosphorylation of S6 kinase was significantly increased compared to wild-type, indicating impairment of TSC1-TSC2 dependent inhibition of TORC1 activity (PMID: 21309039). This variant has been reported in multiple individuals affected with tuberous sclerosis complex (PMID: 20399389, 21910228, 28127866, 29432982, 34252879, 21910228, 28127866). It has been shown that this variant segregates with disease in multiple tuberous sclerosis families (PMID: 21910228, 28127866). This variant has been identified in 1/250330 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Tuberous sclerosis database (TSC2)	RCV000043197	SCV000066998	not provided	Tuberous sclerosis syndrome		no assertion provided	curation
GeneReviews	RCV000459221	SCV002598540	not provided	Tuberous sclerosis 2		no assertion provided	literature only