rs1060503548
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1BP4_Moderate
The NM_000551.4(VHL):āc.62A>Cā(p.Glu21Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000159 in 1,381,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E21K) has been classified as Uncertain significance.
Frequency
Consequence
NM_000551.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VHL | NM_000551.4 | c.62A>C | p.Glu21Ala | missense_variant | 1/3 | ENST00000256474.3 | |
VHL | NM_001354723.2 | c.62A>C | p.Glu21Ala | missense_variant | 1/3 | ||
VHL | NM_198156.3 | c.62A>C | p.Glu21Ala | missense_variant | 1/2 | ||
VHL | NR_176335.1 | n.132A>C | non_coding_transcript_exon_variant | 1/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VHL | ENST00000256474.3 | c.62A>C | p.Glu21Ala | missense_variant | 1/3 | 1 | NM_000551.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 0.0000159 AC: 22AN: 1381672Hom.: 0 Cov.: 32 AF XY: 0.0000162 AC XY: 11AN XY: 679226
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Chuvash polycythemia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 27, 2023 | - - |
Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 21 of the VHL protein (p.Glu21Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with erythrocytosis or clear-cell type renal cell carcinoma (PMID: 22683710, 29790589). ClinVar contains an entry for this variant (Variation ID: 411957). 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 not expected to disrupt VHL protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 25, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal history of clear cell renal carcinoma or erythrocytosis (Pea-Llopis et al., 2012; Oliveira et al., 2018); This variant is associated with the following publications: (PMID: 22683710, 22076155, 29790589) - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 29, 2024 | The p.E21A variant (also known as c.62A>C), located in coding exon 1 of the VHL gene, results from an A to C substitution at nucleotide position 62. The glutamic acid at codon 21 is replaced by alanine, an amino acid with dissimilar properties. This alteration was identified in one individual diagnosed with renal cell carcinoma (Peña-Llopis S et al. Nat. Genet. 2012 Jun;44:751-9). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at