ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.4936G>A (p.Val1646Met)

dbSNP: rs1064796970
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000480140 SCV000574252 likely pathogenic not provided 2023-03-22 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); A different missense change at this residue (V1646G) has been reported in the published literature (Coevoets et al., 2009; Hoogeveen-Westerveld et al., 2011); This variant is associated with the following publications: (PMID: 18466115, 34992632, 32461669, 21309039, 18854862)
Invitae RCV000555170 SCV000644581 pathogenic Tuberous sclerosis 2 2022-11-01 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 424444). This missense change has been observed in individual(s) with clinical features of tuberous sclerosis complex (PMID: 21520333; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1646 of the TSC2 protein (p.Val1646Met).
Genome-Nilou Lab RCV000555170 SCV002041009 pathogenic Tuberous sclerosis 2 2021-11-07 criteria provided, single submitter clinical testing
3billion RCV000555170 SCV004013526 pathogenic Tuberous sclerosis 2 criteria provided, single submitter clinical testing The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.90; 3Cnet: 0.88). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000424444 / PMID: 32461669) and different missense changes at the same codon (p.Val1646Gly, p.Val1646Leu / ClinVar ID: VCV001472268, VCV001490108 / PMID: 18854862) have been previously reported as pathogenic/likely pathogenic with strong evidence. The variant has been observed in at least two similarly affected unrelated individuals (PMID: 32461669, 34992632). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID: 34992632). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

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