ClinVar Miner

Submissions for variant NM_000368.4(TSC1):c.737G>A (p.Arg246Lys) (rs118203436)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000724695 SCV000232537 uncertain significance not provided 2015-03-30 criteria provided, single submitter clinical testing
GeneDx RCV000724695 SCV000243491 likely pathogenic not provided 2018-03-16 criteria provided, single submitter clinical testing p.Arg246Lys (R246K) AGG>AAG: c.737 G>A in exon 8 of the TSC1 gene (NM_000368.4). A variant that is likely pathogenic has been identified in the TSC1 gene. The c.737 G>A variant was identified previously in two individuals with tuberous sclerosis complex (TSC) (Nellist et al., 2009). Parental studies were not performed, and functional studies suggested that this missense variant did not impact TSC1 protein function; however, the authors hypothesized that the c.737 G>A variant may be a pathogenic mutation because the splice models predicted it may disrupt the splice donor site (Nellist et al., 2009). The c.737 G>A variant has also been observed de novo without confirmed parentage in multiple unrelated patients with TSC in published literature (Avgeris et al., 2017; TSC1 LOVD database). The c.737 G>A variant is not observed in large population cohorts (Lek et al., 2016). Multiple in silico algorithms predict that c.737 G>A destroys the natural splice donor site in intron 8 and leads to abnormal splicing. However, in the absence of RNA studies, the actual effect of this sequence change is unknown. If c.737 G>A does not alter splicing, it will result in the R246K missense change. The R246K variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. 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). However, in silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae RCV000821093 SCV000961836 pathogenic Tuberous sclerosis 1 2019-08-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with lysine at codon 246 of the TSC1 protein (p.Arg246Lys). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and lysine. This variant also falls at the last nucleotide of exon 8 of the TSC1 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with tuberous sclerosis, has been reported to be de novo in at least one affected individual (PMID: 18830229, 29196670), and was also observed to segregate with tuberous sclerosis in a family (Invitae). ClinVar contains an entry for this variant (Variation ID: 49094). Experimental studies have shown that this missense change did not impact TSC1 protein function in terms of protein expression and inhibition of phophorylation, but the effect of this variant on splicing was not examined (PMID: 18830229, 21309039). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
Tuberous sclerosis database (TSC1) RCV000042348 SCV000066137 not provided Tuberous sclerosis syndrome no assertion provided curation

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