7-76302886-GC-GCC
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_001540.5(HSPB1):c.180dupC(p.Ala61ArgfsTer100) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000308 in 1,559,206 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001540.5 frameshift
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152040Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000620 AC: 1AN: 161418Hom.: 0 AF XY: 0.0000112 AC XY: 1AN XY: 89614
GnomAD4 exome AF: 0.0000320 AC: 45AN: 1407166Hom.: 0 Cov.: 31 AF XY: 0.0000258 AC XY: 18AN XY: 696614
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152040Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74274
ClinVar
Submissions by phenotype
not provided Pathogenic:2
- -
The c.180dupC variant in the HSPB1 gene causes a frameshift starting with codon Alanine 61, changes this amino acid to an Arginine residue and creates a premature Stop codon at position 100 of the new reading frame, denoted p.Ala61ArgfsX100. This variant is predicted to cause loss of normal protein function through protein truncation, as the last 145 amino acids of the HSPB1 protein are lost and replaced with 99 incorrect amino acids. Multiple variants are noted in the last 145 amino acid residues of the HSPB1 protein in the Human Gene Mutation Database in association with HSPB1-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -
HSPB1-related disorder Pathogenic:1
The HSPB1 c.180dupC variant is predicted to result in a frameshift and premature protein termination (p.Ala61Argfs*100). This variant has been reported in an individual with distal hereditary motor neuropathy (dHMN); and the functional analysis did not show expression of the protein upon HSPB1 staining in HeLa cells (F13 in Table 1 of Echaniz-Laguna et al. 2017. PubMed ID: 28144995). This variant is reported in 0.0040% of alleles in individuals of South Asian descent in gnomAD. Frameshift variants in HSPB1 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -
Charcot-Marie-Tooth disease axonal type 2F Pathogenic:1
This sequence change creates a premature translational stop signal (p.Ala61Argfs*100) in the HSPB1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 145 amino acid(s) of the HSPB1 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with autosomal dominant distal hereditary motor neuropathy (PMID: 28144995). ClinVar contains an entry for this variant (Variation ID: 423339). This variant is located in a region of the HSPB1 protein where a significant number of HSPB1 nonsense and frameshift mutations have been reported in association with autosomal dominant HSPB1-related neuropathies (PMID: 22734906, 28144995, 33686258). For these reasons, this variant has been classified as Pathogenic. -
Neuronopathy, distal hereditary motor, type 2B Pathogenic:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at