7-76304007-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_001540.5(HSPB1):c.452C>T(p.Thr151Ile) variant causes a missense change involving the alteration of a non-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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T151P) has been classified as Uncertain significance.
Frequency
Consequence
NM_001540.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HSPB1 | NM_001540.5 | c.452C>T | p.Thr151Ile | missense_variant | 3/3 | ENST00000248553.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HSPB1 | ENST00000248553.7 | c.452C>T | p.Thr151Ile | missense_variant | 3/3 | 1 | NM_001540.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 33
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth disease axonal type 2F Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 151 of the HSPB1 protein (p.Thr151Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with distal hereditary motor neuropathy or Charcot-Marie-Tooth disease (PMID: 15122254, 18325928, 28144995, 29381233). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7480). 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) performed at Invitae indicates that this missense variant is expected to disrupt HSPB1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. - |
Neuronopathy, distal hereditary motor, type 2B Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2004 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2024 | HSPB1: PP1:Strong, PM1, PM2, PS4:Moderate - |
Charcot-Marie-Tooth disease Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Genetics Laboratory, London Health Sciences Centre | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at