rs869025636
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000551.4(VHL):c.340G>A(p.Gly114Ser) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G114C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000551.4 missense, splice_region
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
VHL | NM_000551.4 | c.340G>A | p.Gly114Ser | missense_variant, splice_region_variant | 1/3 | ENST00000256474.3 | NP_000542.1 | |
VHL | NM_001354723.2 | c.340G>A | p.Val114Ile | missense_variant, splice_region_variant | 1/3 | NP_001341652.1 | ||
VHL | NM_198156.3 | c.340G>A | p.Val114Met | missense_variant, splice_region_variant | 1/2 | NP_937799.1 | ||
VHL | NR_176335.1 | n.410G>A | splice_region_variant, non_coding_transcript_exon_variant | 1/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
VHL | ENST00000256474.3 | c.340G>A | p.Gly114Ser | missense_variant, splice_region_variant | 1/3 | 1 | NM_000551.4 | ENSP00000256474.3 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 24, 2020 | This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that while this missense change does not affect microtubule stabilization, it does exhibit disrupted microtubule turnover, reduced assembly of the VCB-Cul2 complex, and decreased HIF-1 alpha binding and ubiquitination (PMID: 11865071, 12510195, 20855504). Other missense substitutions at this codon (p.Gly114Arg and p.Gly114Cys) have been reported in individuals affected with VHL syndrome (PMID: 7728151, 27527340, 7987306). This suggests that the glycine residue is critical for VHL protein function and that other missense substitutions at this position may also be pathogenic. This variant has been reported in individuals and families affected with von Hippel-Lindau (VHL) syndrome, or VHL-associated lesions (PMID: 20660572, 23407287, 15002726, Invitae). This variant is also known as c.553G>A in the literature. This sequence change replaces glycine with serine at codon 114 of the VHL protein (p.Gly114Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant also falls at the last nucleotide of exon 1 of the VHL coding sequence, which is part of the consensus splice site for this exon. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 14, 2023 | The p.G114S pathogenic mutation (also known as c.340G>A), located in coding exon 1 of the VHL gene, results from a G to A substitution at nucleotide position 340. The glycine at codon 114 is replaced by serine, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 1 and may have some effect on normal mRNA splicing. In functional studies, this alteration was shown to reduce binding and decrease ability to ubiquinate a critical transcription factor HIF1-alpha (Hansen WJ et al. Mol Cell Biol, 2002 Mar;22:1947-60). In addition, this alteration was shown to moderately decrease microtubule regulatory functions compared to the wildtype VHL protein (Thoma CR et al. J Cell Biol, 2010 Sep;190(6):991-1003). This alteration has been reported in multiple individuals with features of VHL and/or a clinical diagnosis of VHL (Loughrey PB et al. Endocr Relat Cancer, 2022 Oct;29:R157-R172; Petenuci J et al. Clin Endocrinol (Oxf), 2021 Jul;95:117-124; Krauss T et al. Endocr Relat Cancer, 2018 Sep;25:783-793; Erlic Z et al. Endocr Relat Cancer, 2010 Dec;17:875-83). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site. This amino acid position is highly conserved in available vertebrate species. In addition, as a missense substitution this is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at