chr3-10142124-G-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000551.4(VHL):c.277G>A(p.Gly93Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000069 in 1,448,564 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G93C) has been classified as Pathogenic.
Frequency
Consequence
NM_000551.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VHL | NM_000551.4 | c.277G>A | p.Gly93Ser | missense_variant | 1/3 | ENST00000256474.3 | |
VHL | NM_001354723.2 | c.277G>A | p.Gly93Ser | missense_variant | 1/3 | ||
VHL | NM_198156.3 | c.277G>A | p.Gly93Ser | missense_variant | 1/2 | ||
VHL | NR_176335.1 | n.347G>A | non_coding_transcript_exon_variant | 1/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VHL | ENST00000256474.3 | c.277G>A | p.Gly93Ser | missense_variant | 1/3 | 1 | NM_000551.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 6.90e-7 AC: 1AN: 1448564Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1AN XY: 721096
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Von Hippel-Lindau syndrome Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genomics Labs, University Health Network | Dec 15, 2021 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Feb 26, 2016 | - - |
Pheochromocytoma Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 09, 2002 | - - |
Chuvash polycythemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 30, 2021 | - - |
Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 09, 2022 | For these reasons, this variant has been classified as Pathogenic. 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 VHL protein function. ClinVar contains an entry for this variant (Variation ID: 2237). This variant is also known as c.490G>A. This missense change has been observed in individual(s) with von Hippel-Lindau (VHL) syndrome (PMID: 8707293, 9329368, 12000816, 17661816, 17922902). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 93 of the VHL protein (p.Gly93Ser). - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 05, 2022 | The p.G93S pathogenic mutation (also known as c.277G>A), located in coding exon 1 of the VHL gene, results from a G to A substitution at nucleotide position 277. The glycine at codon 93 is replaced by serine, an amino acid with similar properties. This alteration has been reported in families with Von Hippel-Lindau (VHL) with pheochromocytomas as well as in individuals with isolated pheochromocytomas (Zbar B et al. Hum Mutat. 1996;8(4):348-57; Neumann HP et al. N Engl J Med. 2002 May 9;346(19):1459-66). Of note, this alteration is also known as c.490G>A in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration 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