rs118203345
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PM5PP2PP3_StrongPP5_Moderate
The NM_000368.5(TSC1):c.182T>G(p.Leu61Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L61P) has been classified as Pathogenic.
Frequency
Consequence
NM_000368.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TSC1 | NM_000368.5 | c.182T>G | p.Leu61Arg | missense_variant | 4/23 | ENST00000298552.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TSC1 | ENST00000298552.9 | c.182T>G | p.Leu61Arg | missense_variant | 4/23 | 1 | NM_000368.5 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Tuberous sclerosis 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 09, 2016 | Experimental studies have shown that this missense change results in reduced TSC1 protein levels, reduced inhibition of TORC1 activity, and altered intracellular expression patterns (PMID: 22161988). A different missense substitution at this codon (p.Leu61Pro) has been also observed in individuals with TSC and has been determined to be likely pathogenic (PMID: 19747374, 21309039). This suggests that the leucine residue is critical for TSC1 protein function. In summary, this variant has been shown to disrupt TSC1 protein function and it occurs at an amino acid position where a different likely pathogenic variant has been previously described. However, the available segregation evidence is limited. For these reasons, this change has been classified as Likely Pathogenic. This variant has been reported in a family affected with tuberous sclerosis complex (TSC) (PMID: 22161988). Although it is reported to co-segregate with disease, details about the family were not provided and, therefore, it is not possible to independently assess this claim. This variant was also observed in another individual diagnosed with TSC (PMID: 22867869). This variant is not present in population databases (rs118203345, ExAC no frequency). This sequence change replaces leucine with arginine at codon 61 of the TSC1 protein (p.Leu61Arg). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and arginine. - |
Tuberous sclerosis syndrome Other:1
not provided, no classification provided | curation | Tuberous sclerosis database (TSC1) | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at