rs1322586198
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PP2PP3_StrongBS2
The ENST00000298552.9(TSC1):c.692C>T(p.Pro231Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P231R) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000298552.9 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TSC1 | NM_000368.5 | c.692C>T | p.Pro231Leu | missense_variant | 8/23 | ENST00000298552.9 | NP_000359.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TSC1 | ENST00000298552.9 | c.692C>T | p.Pro231Leu | missense_variant | 8/23 | 1 | NM_000368.5 | ENSP00000298552 | P4 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152124Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251410Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135880
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461836Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 727218
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152124Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74320
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 10, 2022 | The TSC1 c.692C>T; p.Pro231Leu variant (rs1322586198) is not reported in individuals with Tuberous sclerosis-1 but was detected in a cohort affected with autism spectrum disorder (Kelleher 2012). This variant is also reported in ClinVar (Variation ID: 486585) and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The proline at codon 231 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.865). Due to limited information, the clinical significance of the p.Pro231Leu variant is uncertain at this time. References: Kelleher RJ 3rd et al. High-throughput sequencing of mGluR signaling pathway genes reveals enrichment of rare variants in autism. PLoS One. 2012;7(4):e35003. PMID: 22558107. - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 03, 2024 | Identified in individual(s) with autism spectrum disorder (PMID: 22558107); 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: 23514105, 22558107) - |
Tuberous sclerosis 1 Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 04, 2023 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 03, 2023 | The p.P231L variant (also known as c.692C>T), located in coding exon 6 of the TSC1 gene, results from a C to T substitution at nucleotide position 692. The proline at codon 231 is replaced by leucine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at